Compounds and compositions for treating conditions associated with nlrp activity

ABSTRACT

In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured: Formula AA or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula A can be as defined anywhere herein.

TECHNICAL FIELD

This disclosure features chemical entities (e.g., a compound that modulates (e.g., antagonizes) NLRP3, or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that are useful, e.g., for treating a condition, disease or disorder in which a decrease or increase in NLRP3 activity (e.g., an increase, e.g., a condition, disease or disorder associated with NLRP3 signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder in a subject (e.g., a human). This disclosure also features compositions as well as other methods of using and making the same.

The present disclosure also relates to, in part, methods and compositions for treating anti-TNFα resistance in a subject with an NLRP3 antagonist. The present disclosure also relates, in part, to methods, combinations and compositions for treating TFNα related diseases and anti-TNFα resistance in a subject that include administration of an NLRP3 antagonist, an NLRP3 antagonist and an anti-TNFα agent, or a composition encompassing an NLRP3 antagonist and an anti-TNFα agent.

BACKGROUND

The NLRP3 inflammasome is a component of the inflammatory process and its aberrant activation is pathogenic in inherited disorders such as the cryopyrin associated periodic syndromes (CAPS). The inherited CAPS Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) and neonatal onset multi-system inflammatory disease (NOMID) are examples of indications that have been reported to be associated with gain of function mutations in NLRP3.

NLRP3 can form a complex and has been implicated in the pathogenesis of a number of complex diseases, including but not limited to metabolic disorders such as type 2 diabetes, atherosclerosis, obesity and gout, as well as diseases of the central nervous system, such as Alzheimer's disease and multiple sclerosis and Amyotrophic Lateral Sclerosis and Parkinson disease, lung disease, such as asthma and COPD and pulmonary idiopathic fibrosis, liver disease, such as NASH syndrome, viral hepatitis and cirrhosis, pancreatic disease, such as acute and chronic pancreatitis, kidney disease, such as acute and chronic kidney injury, intestinal disease such as Crohn's disease and Ulcerative Colitis, skin disease such as psoriasis, musculoskeletal disease such as scleroderma, vessel disorders, such as giant cell arteritis, disorders of the bones, such as Osteoarthritis , osteoporosis and osteopetrosis disorders eye disease, such as glaucoma and macular degeneration, diseased caused by viral infection such as HIV and AIDS, autoimmune disease such as Rheumatoid Arthritis, Systemic Lupus Erythematosus, Autoimmune Thyroiditis, Addison's disease, pernicious anemia, cancer and aging.

In light of the above, it would be desirable to provide compounds that modulate (e.g., antagonize) NLRP3.

Several patients having inflammatory or autoimmune diseases are treated with anti-TNFα agents. A subpopulation of such patients develop resistance to treatment with the anti-TNFα agents. It is desirable to develop methods for reducing a patient's resistance to anti-TNFα agents. In light of the this, it would also be desirable to provide alternative therapies for treating inflammatory or autoimmune diseases (for example NLRP3 inflammasome inhibitors) to avoid or minimise the use of anti-TNFα agents.

Intestinal bowel disease (IBD), encompassing Ulcerative Colitis (UC) and Crohn's disease (CD), are chronic diseases characterized by barrier dysfunction and uncontrolled inflammation and mucosal immune reactions in the gut. A number of inflammatory pathways have been implicated in the progression of IBD, and anti-inflammatory therapy such as tumor necrosis factor-alpha (TNF-α) blockade has shown efficacy in the clinic (Rutgeerts P et a1 N Engl J Med 2005; 353:2462-76). Anti-TNFα therapies, however, do not show complete efficacy, however, other cytokines such as IL-1β, IL-6, IL-12, IL-18, IL-21, and IL-23 have been shown to drive inflammatory disease pathology in IBD (Neurath M F Nat Rev Immunol 2014; 14; 329-42). IL-1β and IL-18 are produced by the NLRP3 inflammasome in response to pathogenic danger signals, and have been shown to play a role in IBD. Anti-IL-1β therapy is efficacious in patients with IBD driven by genetic mutations in CARD8 or IL-10R (Mao L et al, J Clin Invest 2018; 238:1793-1806, Shouval D S et al, Gastroenterology 2016; 151:1100-1104), IL-18 genetic polymorphisms have been linked to UC (Kanai Tet al, Curr Drug Targets 2013; 14:1392-9), and NLRP3 inflammasome inhibitors have been shown to be efficacious in murine models of IBD (Perera A P et al, Sci Rep 2018; 8:8618). Resident gut immune cells isolated from the lamina propria of IBD patients can produce IL-1β, either spontaneously or when stimulated by LPS, and this IL-1β production can be blocked by the ex vivo addition of a NLRP3 antagonist. Based on strong clinical and preclinical evidence showing that inflammasome-driven IL-1β and IL-18 play a role in IBD pathology, it is clear that NLRP3 inflammasome inhibitors could be an efficacious treatment option for UC, Crohn's disease, or subsets of IBD patients. These subsets of patients could be defined by their peripheral or gut levels of inflammasome related cytokines including IL-1β, IL-6, and IL-18, by genetic factors that pre-dispose IBD patients to having NLRP3 inflammasome activation such as mutations in genes including ATG16 L1, CARD8, IL-10R, or PTPN2 (Saitoh T et al, Nature 2008; 456:264, Spalinger M R, Cell Rep 2018; 22:1835), or by other clinical rationale such as non-response to TNF therapy.

Though anti-TNF therapy is an effective treatment option for Crohn's disease, 40% of patients fail to respond. One-third of non-responsive CD patients fail to respond to anti-TNF therapy at the onset of treatment, while another third lose response to treatment over time (secondary non-response). Secondary non-response can be due to the generation of anti-drug antibodies, or a change in the immune compartment that desensitizes the patient to anti-TNF (Ben-Horin S et al, Autoimmun Rev 2014; 13:24-30, Steenholdt C et a1 Gut 2014; 63:919-27). Anti-TNF reduces inflammation in IBD by causing pathogenic T cell apoptosis in the intestine, therefore eliminating the T cell mediated inflammatory response (Van den Brande et a1 Gut 2007:56:509-17). There is increased NLRP3 expression and increased production of IL-1β in the gut of TNF-non-responsive CD patients (Leal R F et a1 Gut 2015; 64:233-42) compared to TNF-responsive patients, suggesting NLRP3 inflammasome pathway activation. Furthermore, there is increased expression of TNF-receptor 2 (TNF-R2), which allows for TNF-mediated proliferation of T cells (Schmitt H et a1 Gut 2018; 0:1-15). IL-1β signaling in the gut promotes T cell differentiation toward Th1/17 cells which can escape anti-TNF-α mediated apoptosis. It is therefore likely that NLRP3 inflammasome activation can cause non-responsiveness in CD patients to anti-TNF-α therapy by sensitizing pathogenic T cells in the gut to anti-TNF-α mediated apoptosis. Experimental data from immune cells isolated from the gut of TNF-resistant Crohn's patients show that these cells spontaneously release IL-1β, which can be inhibited by the addition of an NLRP3 antagonist. NLRP3 inflammasome antagonists—in part by blocking IL-1β secretion—would be expected to inhibit the mechanism leading to anti-TNF non-responsiveness, re-sensitizing the patient to anti-TNF therapy. In IBD patients who are naive to anti-TNF therapy, treatment with an NLRP3 antagonist would be expected to prevent primary- and secondary-non responsiveness by blocking the mechanism leading to non-response.

NLRP3 antagonists that are efficacious locally in the gut can be efficacious drugs to treat IBD; in particular in the treatment of TNF-resistant CD alone or in combination with anti-TNF therapy. Systemic inhibition of both IL-1β and TNF-α has been shown to increase the risk of opportunistic infections (Genovese M C et al, Arthritis Rheum 2004; 50:1412), therefore, only blocking the NLRP3 inflammasome at the site of inflammation would reduce the infection risk inherent in neutralizing both IL-1β and TNF-α. NLRP3 antagonists that are potent in NLRP3-inflammasome driven cytokine secretion assays in cells, but have low permeability in vitro in a permeability assay such as an MDCK assay, have poor systemic bioavailability in a rat or mouse pharmacokinetic experiment, but high levels of compound in the colon and/or small intestine could be a useful therapeutic option for gut restricted purposes.

In light of the above, the present invention also provides alternative therapies for the treatment of inflammatory or autoimmune diseases, including IBD, that solves the above problems associated with anti-TNFα agents.

SUMMARY

This disclosure features chemical entities (e.g., a compound that modulates (e.g., antagonizes) NLRP3, or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that are useful, e.g., for treating a condition, disease or disorder in which a decrease or increase in NLRP3 activity (e.g., an increase, e.g., a condition, disease or disorder associated with NLRP3 signaling).

In some embodiments, provided herein is a compound of Formula AA

or a pharmaceutically acceptable salt thereof, wherein the variables in Formula AA can be as defined anywhere herein.

This disclosure also features compositions as well as other methods of using and making the same.

An “antagonist” of NLRP3 includes compounds that inhibit the ability of NLRP3 to induce the production of IL-1β and/or IL-18 by directly binding to NLRP3, or by inactivating, destabilizing, altering distribution, of NLRP3 or otherwise.

In one aspect, pharmaceutical compositions are featured that include a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same) and one or more pharmaceutically acceptable excipients.

In one aspect, methods for modulating (e.g., agonizing, partially agonizing, antagonizing) NLRP3 activity are featured that include contacting NLRP3 with a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same). Methods include in vitro methods, e.g., contacting a sample that includes one or more cells comprising NLRP3, as well as in vivo methods.

In a further aspect, methods of treatment of a disease in which NLRP3 signaling contributes to the pathology and/or symptoms and/or progression of the disease are featured that include administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).

In a further aspect, methods of treatment are featured that include administering to a subject a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same), wherein the chemical entity is administered in an amount effective to treat a disease in which NLRP3 signaling contributes to the pathology and/or symptoms and/or progression of the disease, thereby treating the disease.

Embodiments can include one or more of the following features.

The chemical entity can be administered in combination with one or more additional therapies with one or more agents suitable for the treatment of the condition, disease or disorder.

Examples of the indications that may be treated by the compounds disclosed herein include but are not limited to metabolic disorders such as type 2 diabetes, atherosclerosis, obesity and gout, as well as diseases of the central nervous system, such as Alzheimer's disease and multiple sclerosis and Amyotrophic Lateral Sclerosis and Parkinson disease, lung disease, such as asthma and COPD and pulmonary idiopathic fibrosis, liver disease, such as NASH syndrome, viral hepatitis and cirrhosis, pancreatic disease, such as acute and chronic pancreatitis, kidney disease, such as acute and chronic kidney injury, intestinal disease such as Crohn's disease and Ulcerative Colitis, skin disease such as psoriasis, musculoskeletal disease such as scleroderma, vessel disorders, such as giant cell arteritis, disorders of the bones, such as osteoarthritis , osteoporosis and osteopetrosis disorders, eye disease, such as glaucoma and macular degeneration, diseases caused by viral infection such as HIV and AIDS, autoimmune disease such as rheumatoid arthritis, systemic Lupus erythematosus, autoimmune thyroiditis; Addison's disease, pernicious anemia, cancer and aging.

The methods can further include identifying the subject.

The present invention is also relates to the Applicant's discovery that inhibition of NLRP3 inflammasomes can increase a subject's sensitivity to an anti-TNFα agent or can overcome resistance to an anti-TNFα agent in a subject, or indeed provide an alternative therapy to anti-TNFα agents.

Provided herein are methods of treating a subject that include: (a) identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity and/or expression as compared to a reference level; and (b) administering to the identified subject a therapeutically effective amount of an compound of Formula I or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Provided herein are methods for the treatment of inflammatory or autoimmune disease including IBD, such as UC and CD in a subject in need thereof, comprising administering to said subject a therapeutically effective amount a compound for Formula I or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, wherein the NLRP3 antagonist is a gut-targeted NLRP3 antagonist.

Provided herein are methods of treating a subject in need thereof, that include: (a) identifying a subject having resistance to an anti-TNFα agent; and (b) administering a treatment comprising a therapeutically effective amount of a compound for Formula I, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to the identified subject.

Provided herein are methods of treating a subject in need thereof, that include: administering a treatment comprising a therapeutically effective amount of a compound for Formula I or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject identified as having resistance to an anti-TNFα agent.

Provided herein are methods of selecting a treatment for a subject in need thereof, that include: (a) identifying a subject having resistance to an anti-TNFα agent; and (b) selecting for the identified subject a treatment comprising a therapeutically effective amount of a compound for Formula I or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Provided herein are methods of selecting a treatment for a subject in need thereof, that include selecting a treatment comprising a therapeutically effective amount of a compound for Formula I or a pharmaceutically acceptable salt, solvate, or co-crystal thereof for a subject identified as having resistance to an anti-TNFα agent.

In some embodiments of any of the methods described herein, the treatment further includes a therapeutically effective amount of an anti-TNFα agent, in addition to the NLRP3 antagonist.

Other embodiments include those described in the Detailed Description and/or in the claims.

Additional Definitions

To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties.

As used herein, the term “NLRP3” is meant to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous NLRP3 molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

“API” refers to an active pharmaceutical ingredient.

The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a chemical entity (e.g., a compound exhibiting activity as a modulator of NLRP3, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof;) being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.

The term “excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

The term “pharmaceutically acceptable salt” may refer to pharmaceutically acceptable addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. The term “pharmaceutically acceptable salt” may also refer to pharmaceutically acceptable addition salts prepared by reacting a compound having an acidic group with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human.

As used herein, the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment to ameliorating the disease or disorder (i.e. slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms or pathological features thereof). In another embodiment “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter or pathological features of the disease, e.g. including those, which may not be discernible by the subject. In yet another embodiment, “treat”, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g. stabilization of at least one discernible or non-discernible symptom), physiologically (e.g. stabilization of a physical parameter) or both. In yet another embodiment, “treat”, “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder, or of at least one symptoms or pathological features associated thereof. In yet another embodiment, “treat”, “treating” or “treatment” refers to preventing or delaying progression of the disease to a more advanced stage or a more serious condition.

As used herein, the term “prevent”, “preventing” or “prevention” in connection to a disease or disorder refers to the prophylactic treatment of a subject who is at risk of developing a condition (e.g., specific disease or disorder or clinical symptom thereof) resulting in a decrease in the probability that the subject will develop the condition.

The terms “hydrogen” and “H” are used interchangeably herein.

The term “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

The term “alkyl” refers to a hydrocarbon chain that may be a straight chain or branched chain, saturated or unsaturated, containing the indicated number of carbon atoms. For example, C₁₋₁₀ indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl.

The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halo.

The term “alkoxy” refers to an —O-alkyl radical (e.g., —OCH₃).

The term “carbocyclic ring” as used herein includes an aromatic or nonaromatic cyclic hydrocarbon group having 3 to 10 carbons, such as 3 to 8 carbons, such as 3 to 7 carbons, which may be optionally substituted. Examples of carbocyclic rings include five-membered, six-membered, and seven-membered carbocyclic rings.

The term “heterocyclic ring” refers to an aromatic or nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, or 3 atoms of each ring may be substituted by a substituent. Each ring of a bicyclic or tricyclic heterocyclic ring is selected from saturated, unsaturated, and aromatic (carbocyclic aromatic and heteroaromatic) rings. Examples of heterocyclic rings include five-membered, six-membered, and seven-membered heterocyclic rings.

The term “cycloalkyl” as used herein includes an nonaromatic cyclic, bicylic, fused, or spiro hydrocarbon radical having 3 to 10 carbons, such as 3 to 8 carbons, such as 3 to 7 carbons, wherein the cycloalkyl group which may be optionally substituted. Examples of cycloalkyls include five-membered, six-membered, and seven-membered rings. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

The term “heterocycloalkyl” refers to a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic fused or spiro ring system radical wherein at least one of the rings in the ring system (1) is nonaromatic and (2) includes 1-3 heteroatoms. When the ring system is bicyclic, 1-6 heteroatom ring members are present; and when the ring system is tricyclic, 1-9 heteroatom ring members are present. The ring heteroatoms are selected from O, N, and S (e.g., the ring system includes carbon atoms and 1-3, 1-6, or 1-9 heteroatoms selected from N, O, and S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, or 3 atoms of each ring may be substituted by a substituent. Examples of heterocycloalkyls include five-membered, six-membered, seven-membered, eight-membered, and ten-membered rings. Examples include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, (3aR,6aS)-hexahydro-1H-thieno[3,4-d]imidazole, 1,2,3,4-tetrahydroisoquinoline, and the like.

The term “aryl” is intended to mean an aromatic ring radical containing 6 to 10 ring carbons. Examples include phenyl and naphthyl.

The term “heteroaryl” is intended to mean an aromatic ring system containing 5 to 14 aromatic ring atoms that may be a single ring, two fused rings or three fused rings wherein at least one aromatic ring atom is a heteroatom selected from, but not limited to, the group consisting of O, S and N. Examples include furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like. Examples also include carbazolyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, triazinyl, indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl. phenazinyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl, imidazopyridinyl, benzothienyl, benzofuranyl, isobenzofuran and the like.

The term “hydroxy” refers to an OH group.

The term “amino” refers to an NH₂ group.

The term “oxo” refers to O. By way of example, substitution of a CH₂ a group with oxo gives a C═O group.

As used herein, the terms “the ring A” or “A” are used interchangeably to denote

in formula AA, wherein the bond that is shown as being broken by the wavy line

connects A to the S(O)(NHR³)═N moiety of Formula AA.

As used herein, the terms “the ring B” or “B” are used interchangeably to denote

in formula AA wherein the bond that is shown as being broken by the wavy line

connects B to the NH(CO) group of Formula AA.

As used herein, the term “the optionally substituted ring A” is used to denote

in formula AA, wherein the bond that is shown as being broken by the wavy line

connects A to the S(O)(NHR³)═N moiety of Formula AA.

As used herein, the term “the substituted ring B” is used to denote

in formula AA, wherein the bond that is shown as being broken by the wavy line

connects B to the NH(CO) group of Formula AA.

As used herein, the recitation “S(O₂)”, alone or as part of a larger recitation, refers to the group

In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include ¹³C and ¹⁴C.

The scope of the compounds disclosed herein includes tautomeric form of the compounds. Thus, by way of example, a compound that is represented as containing the moiety

is also intended to include the tautomeric form containing the moiety

In addition, by way of example, a compound that is represented as containing the moiety

is also intended to include the tautomeric form containing the moiety

Non-limiting exemplified compounds of the formulae described herein include a stereogenic sulfur atom and optionally one or more stereogenic carbon atoms. This disclosure provides examples of stereoisomer mixtures (e.g., racemic mixture of enantiomers; mixture of diastereomers). This disclosure also describes and exemplifies methods for separating individual components of said stereoisomer mixtures (e.g., resolving the enantiomers of a racemic mixture). In cases of compounds containing only a stereogenic sulfur atom, resolved enantiomers are graphically depicted using one of the two following formats: formulas A/B (hashed and solid wedge three-dimensional representation); and formula C (“flat structures with *-labelled stereogenic sulfur).

In reaction schemes showing resolution of a racemic mixture, Formulas A/B and C are intended only to convey that the constituent enantiomers were resolved in enantiopure pure form (about 98% ee or greater). The schemes that show resolution products using the formula A/B format are not intended to disclose or imply any correlation between absolute configuration and order of elution. Some of the compounds shown in the tables below are graphically represented using the formula A/B format. However, with the exception of compounds 181a and 181b, the depicted stereochemistry shown for each of the tabulated compounds drawn in the formula A/B format is a tentative assignment and based, by analogy, on the absolute stereochemistry assigned to compounds 181b (see, e.g., FIGS. 1 and 2 ).

The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 depicts ball-and-stick representations of two crystallographically independent molecules of compound 181a in the asymmetrical unit.

FIG. 2 depicts ball-and-stick representations of two crystallographically independent molecules of compound 181b in the asymmetrical unit.

FIG. 3 depicts the layout of the microplate used in an hTHP-1 assay.

FIG. 4 : Expression levels of RNA encoding NLRP3 in Crohn's Disease patients who are responsive and non-responsive to infliximab.

FIG. 5 : Expression levels of RNA encoding IL-1β in Crohn's Disease patients who are responsive and non-responsive to infliximab.

FIG. 6 : Expression levels of RNA encoding NLRP3 in Ulcerative Colitis (UC) patients who are responsive and non-responsive to infliximab.

FIG. 7 : Expression levels of RNA encoding IL-1β in Ulcerative Colitis (UC) patients who are responsive and non-responsive to infliximab.

DETAILED DESCRIPTION

In some embodiments, provided herein is a compound of Formula AA:

wherein

m=0, 1, or 2;

n=0, 1, or 2;

o=1 or 2;

p=0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₆-C₁₀ monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C₆-C₁₀ monocyclic or bicyclic aryl; wherein at least one R⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA;

R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NR⁸R⁹, C(O)R¹³, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl,

wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);

wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃ alkylene)C₆-C₁₀ aryl, halo, NR⁸R⁹, or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

or one pair of R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹,

wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl,

wherein R⁶ and R⁷ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy that R⁶ or R⁷ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

R¹⁰ is C₁-C₆ alkyl;

each of R⁸ and R⁹ at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR¹¹R¹²;

or R⁸ and R⁹ taken together with the nitrogen they are attached to form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

R¹³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, or —(Z¹—Z²)_(a1)—Z³;

each of R¹¹ and R¹² at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, and —(Z¹—Z²)_(a1)—Z³;

a1 is 0-10 (e.g., 0-4);

each Z¹ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy;

each Z² is independently a bond, NH, N(C₁-C₆ alkyl), —O—, —S—, or 5-10 membered heteroarylene;

Z³ is independently C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

R³ is selected from hydrogen, cyano, hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkyl, and

wherein the C₁-C₂ alkylene group is optionally substituted by oxo;

R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆ alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R⁶,

R¹⁵ is —(Z⁴—Z⁵)_(a2)—Z⁶;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z⁴ is independently selected from —O—, —S—, —NH—, and —N(C₁-C₃ alkyl)-;

provided that the Z⁴ group directly attached to R¹ or R² is —O— or —S—;

each Z⁵ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z⁶ is OH, OC₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, NHC(O)(C₁-C₆ alkyl), NHC(O)(C₁-C₆ alkoxy), or an optionally substituted group selected from the group consisting of:

C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆ alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound of Formula AA:

wherein

m=0, 1, or 2;

n=0, 1, or 2;

o=1 or 2;

p=0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₆-C₁₀ monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C₆-C₁₀ monocyclic or bicyclic aryl; wherein at least one R⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA;

R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NR⁸R⁹, C(O)R¹³, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl,

wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);

wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃ alkylene)C₆-C₁₀ aryl, halo, NR⁸R⁹, or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

or one pair of R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹,

wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl,

wherein R⁶ and R⁷ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy that R⁶ or R⁷ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

R₁₀ is C₁-C₆ alkyl;

each of R⁸ and R⁹ at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₇ cycloalkyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR¹¹R¹²;

or R⁸ and R⁹ taken together with the nitrogen they are attached to form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆ alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

R¹³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, or —(Z¹—Z²)_(a1)—Z³;

each of R¹¹ and R¹² at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, and —(Z¹—Z²)_(a1)—Z³;

a1 is 0-10 (e.g., 0-4);

each Z¹ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy;

each Z² is independently a bond, NH, N(C₁-C₆ alkyl), —O—, —S—, or 5-10 membered heteroarylene;

Z³ is independently C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

R³ is selected from hydrogen and C₁-C₆ alkyl;

R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆ alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R⁶,

R¹⁵ is —(Z⁴—Z⁵)_(a2)—Z⁶;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z⁴ is independently selected from —O—, —S—, —NH—, and —N(C₁-C₃ alkyl)-;

provided that the Z⁴ group directly attached to R¹ or R² is —O— or —S—;

each Z⁵ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z⁶ is OH, OC₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, NHC(O)(C₁-C₆ alkyl), NHC(O)(C₁-C₆ alkoxy), or an optionally substituted group selected from the group consisting of:

C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆ alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

or a pharmaceutically acceptable salt thereof;

provided that the compound is other than:

-   -   In some embodiments, the compound of Formula AA is other than         one of the following compounds:

In some embodiments, provided herein is a compound of Formula AA:

wherein

m=0, 1, or 2;

n=0, 1, or 2;

o=1 or 2;

p=0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₆-C₁₀ monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C₆-C₁₀ monocyclic or bicyclic aryl;

wherein at least one R⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA;

R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO—C₆-C₁₀ aryl, CO(5- to 10-membered heteroaryl); CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, NHCOOCC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl,

wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl;

wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃ alkylene)C₆-C₁₀ aryl, halo, NR⁸R⁹, or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

or one pair of R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹,

wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl,

wherein R⁶ and R⁷ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy that R⁶ or R⁷ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

R¹⁰ is C₁-C₆ alkyl;

each of R⁸ and R⁹ at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR₁₃, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR¹¹R¹²; or R⁸ and R⁹ taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to;

-   R¹³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, or 5- to     10-membered heteroaryl; -   each of R¹¹ and R¹² at each occurrence is independently selected     from hydrogen and C₁-C₆ alkyl;

R³ is selected from hydrogen, cyano, hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkyl, and

wherein the C₁-C₂ alkylene group is optionally substituted by oxo;

R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆ alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R⁶,

R¹⁵ is —(Z⁴—Z⁵)_(a2)—Z⁶;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z⁴ is independently selected from —O—, —S—, —NH—, and —N(C₁-C₃ alkyl)-;

provided that the Z⁴ group directly attached to R¹ or R² is —O— or —S—;

each Z⁵ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z⁶ is OH, OC₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, NHC(O)(C₁-C₆ alkyl), NHC(O)(C₁-C₆ alkoxy), or an optionally substituted group selected from the group consisting of:

C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆ alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound of Formula AA:

wherein

m=0, 1, or 2;

n=0, 1, or 2;

o=1 or 2;

p=0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₆-C₁₀ monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C₆-C₁₀ monocyclic or bicyclic aryl;

wherein at least one R⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA;

R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO—C₆-C₁₀ aryl, CO(5- to 10-membered heteroaryl); CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, NHCOOCC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl,

wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl;

wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃ alkylene)C₆-C₁₀ aryl, halo, NR⁸R⁹, or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

or one pair of R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹,

wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl,

wherein R⁶ and R⁷ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy that R⁶ or R⁷ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

R¹⁰ is C₁-C₆ alkyl;

each of R⁸ and R⁹ at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₇ cycloalkyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR¹¹R¹²; or R⁸ and R⁹ taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to;

-   R¹³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, or 5- to     10-membered heteroaryl; -   each of R¹¹ and R¹² at each occurrence is independently selected     from hydrogen and C₁-C₆ alkyl;

R³ is selected from hydrogen and C₁-C₆ alkyl; and

R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆ alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R⁶,

R¹⁵ is —(Z⁴—Z⁵)_(a2)—Z⁶;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z⁴ is independently selected from —O—, —S—, —NH—, and —N(C₁-C₃ alkyl)-;

provided that the Z⁴ group directly attached to R¹ or R² is —O— or —S—;

each Z⁵ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z⁶ is OH, OC₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, NHC(O)(C₁-C₆ alkyl), NHC(O)(C₁-C₆ alkoxy), or an optionally substituted group selected from the group consisting of:

C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆ alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

or a pharmaceutically acceptable salt thereof;

provided that the compound is other than:

In some embodiments, the compound of Formula AA is other than one of the following compounds:

In some embodiments, provided herein is a compound of Formula AA:

wherein

m=0, 1, or 2;

n=0, 1, or 2;

o=1 or 2;

p=0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₆-C₁₀ monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C₆-C₁₀ monocyclic or bicyclic aryl;

wherein

at least one R⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA;

R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO—C₆-C₁₀ aryl, CO(5- to 10-membered heteroaryl); CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, NHCOOCC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl;

-   -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy         substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²         3- to 7-membered heterocycloalkyl is further optionally         independently substituted with one to three hydroxy, halo,         NR⁸R⁹, or oxo;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl;

or one pair of R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl,

wherein R⁶ and R⁷ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy that R⁶ or R⁷ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

-   -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl), and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl;

-   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹;

-   each of R⁴ and R⁵ is independently selected from hydrogen and C₁-C₆     alkyl;

-   R¹⁰ is C₁-C₆ alkyl;

-   each of R⁸ and R⁹ at each occurrence is independently selected from     hydrogen, C₁-C₆ alkyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl,     S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl     is optionally substituted with one or more hydroxy, halo, C₁-C₆     alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl     or 3- to 7-membered heterocycloalkyl; or R⁸ and R⁹ taken together     with the nitrogen they are attached to form a 3- to 7-membered ring     optionally containing one or more heteroatoms in addition to the     nitrogen they are attached to;

-   R¹³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, or 5- to     10-membered heteroaryl;

-   each of R¹¹ and R¹² at each occurrence is independently selected     from hydrogen and C₁-C₆ alkyl;

-   R³ is selected from hydrogen, cyano, hydroxy, C₁-C₆ alkoxy, C₁-C₆     alkyl, and

wherein the C₁-C₂ alkylene group is optionally substituted by oxo; and

-   R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or     bicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein     each C₁-C₆ alkyl, aryl or heteroaryl is optionally independently     substituted with 1 or 2 R⁶, -   or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound of Formula AA

-   wherein -   m=0, 1, or 2; -   n=0, 1, or 2; -   o=1 or 2; -   p=0, 1, 2, or 3; -   wherein -   A is a 5-10-membered heteroaryl or a C₆-C₁₀ aryl; -   B is a 5-10-membered heteroaryl or a C₆-C₁₀ aryl; -   wherein -   at least one R⁶ is ortho to the bond connecting the B ring to the     NR³(CO) group of Formula AA; -   R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO—C₆-C₁₀ aryl, CO-(5- to 10-membered heteroaryl), CO₂C₁-C₆     alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5-     to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl,     N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to     10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl),     NHCOC₂-C₆ alkynyl, NHCOOC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹,     SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl,     C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl, -   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, and 3-     to 7-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, COOC₁-C₆ alkyl, NR⁸R⁹, CONR⁸R⁹,     3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered     heteroaryl), and OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆     alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3-     to 7-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl;     -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy         substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²         3- to 7-membered heterocycloalkyl is further optionally         independently substituted with one to three hydroxy, halo, or         oxo;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or         5- to 10-membered heteroaryl, of the R¹ or R² C₁-C₆ alkyl, the         R¹ or R² C₁-C₆ haloalkyl, the R¹ or R² C₃-C₇ cycloalkyl, or the         R¹ or R² 3- to 7-membered heterocycloalkyl are optionally         substituted with one or more substituents independently selected         from halo, C₁-C₆ alkyl, oxo, and OC₁-C₆ alkyl; -   or at least one pair of R¹ and R² on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5- to-8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆     alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹,     wherein the C₁-C₆ alkyl and C₁-C₆ alkoxy are optionally substituted     with hydroxy, halo, oxo, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; -   R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl,     OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to     7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅,     SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 3- to 10-membered     heterocycloalkyl, and C₂-C₆ alkenyl, -   wherein R⁶ and R⁷ are each optionally substituted with one or more     substituents independently selected from hydroxy, halo, CN, oxo,     C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3-     to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered     heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆     alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3-     to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy,     and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy     that R⁶ or R⁷ is substituted with is optionally substituted with one     or more hydroxyl, halo, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is     optionally fused to a five- to -seven-membered carbocyclic ring or     heterocyclic ring containing one or two heteroatoms independently     selected from oxygen, sulfur and nitrogen;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 4-to 8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     NR²⁰, and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹; -   each of R⁴ and R⁵ is independently selected from hydrogen and C₁-C₆     alkyl; -   R¹⁰ is C₁-C₆ alkyl; -   each of R⁸ and R⁹ at each occurrence is independently selected from     hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,     (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and     CONR¹¹R¹²; wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl     is optionally substituted with one or more hydroxy, halo, oxo, C₁-C₆     alkoxy, C₂-C₆ alkynyl, CO₂R¹³, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, C₃-C₇ cycloalkyl, or 3- to 7-membered heterocycloalkyl;     or R⁸ and R⁹ taken together with the nitrogen they are attached to     form a 3- to 7-membered ring optionally containing one or more     heteroatoms in addition to the nitrogen they are attached to; -   R¹³ is C₁-C₆ alkyl, C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl; -   each of R¹¹ and R¹² at each occurrence is independently selected     from hydrogen and C₁-C₆ alkyl; -   each R³ is independently selected from hydrogen, cyano, hydroxy,     C₁-C₆ alkoxy, C₁-C₆ alkyl, CO₂C₁-C₆ alkyl, and

wherein the C₁-C₂ alkylene group is optionally substituted with oxo; and

-   R¹⁴ is hydrogen, C₁-C₆ alkyl, 5-10-membered monocyclic or bicyclic     heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆     alkyl, aryl or heteroaryl is optionally independently substituted     with 1, 2, or 3 R⁶; -   or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound of Formula AA

-   wherein -   m=0, 1, or 2; -   n=0, 1, or 2; -   o=1 or 2; -   p=0, 1, 2, or 3; -   wherein -   A is a 5-10-membered heteroaryl or a C₆-C₁₀ aryl; -   B is a 5-10-membered heteroaryl or a C₆-C₁₀ aryl; -   wherein -   at least one R⁶ is ortho to the bond connecting the B ring to the     NR³(CO) group of Formula AA; -   R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO—C₆-C₁₀ aryl, CO-(5- to 10-membered heteroaryl), CO₂C₁-C₆     alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5-     to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl,     N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to     10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl),     NHCOC₂-C₆ alkynyl, NHCOOC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹,     SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl,     C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl, -   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, and 3-     to 7-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, COOC₁-C₆ alkyl, NR⁸R⁹, CONR⁸R⁹,     3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered     heteroaryl), and OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆     alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3-     to 7-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl;     -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy         substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²         3- to 7-membered heterocycloalkyl is further optionally         independently substituted with one to three hydroxy, halo, or         oxo;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, or         5- to 10-membered heteroaryl, of the R¹ or R² C₁-C₆ alkyl, the         R¹ or R² C₁-C₆ haloalkyl, the R¹ or R² C₃-C₇ cycloalkyl, or the         R¹ or R² 3- to 7-membered heterocycloalkyl are optionally         substituted with one or more substituents independently selected         from halo, C₁-C₆ alkyl, oxo, and OC₁-C₆ alkyl; -   or at least one pair of R¹ and R² on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5- to-8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆     alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹,     wherein the C₁-C₆ alkyl and C₁-C₆ alkoxy are optionally substituted     with hydroxy, halo, oxo, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; -   R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl,     OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to     7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅,     SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 3- to 10-membered     heterocycloalkyl, and C₂-C₆ alkenyl, -   wherein R⁶ and R⁷ are each optionally substituted with one or more     substituents independently selected from hydroxy, halo, CN, oxo,     C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3-     to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered     heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆     alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3-     to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy,     and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy     that R⁶ or R⁷ is substituted with is optionally substituted with one     or more hydroxyl, halo, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is     optionally fused to a five- to -seven-membered carbocyclic ring or     heterocyclic ring containing one or two heteroatoms independently     selected from oxygen, sulfur and nitrogen;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5-to 8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹; -   R₁₀ is C₁-C₆ alkyl; -   each of R⁸ and R⁹ at each occurrence is independently selected from     hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl (C═NR¹³)NR¹¹R¹²,     S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein     the C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl is optionally     substituted with one or more hydroxy, halo, oxo, C₁-C₆ alkoxy, C₂-C₆     alkynyl, CO₂R¹³, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇     cycloalkyl, or 3- to 7-membered heterocycloalkyl; or R⁸ and R⁹ taken     together with the nitrogen they are attached to form a 3- to     7-membered ring optionally containing one or more heteroatoms in     addition to the nitrogen they are attached to; -   R¹³ is C₁-C₆ alkyl, C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl; -   each of R¹¹ and R¹² at each occurrence is independently selected     from hydrogen and C₁-C₆ alkyl; -   each R³ is independently selected from hydrogen, cyano, hydroxy,     C₁-C₆ alkoxy, C₁-C₆ alkyl, CO₂C₁-C₆ alkyl, and

wherein the C₁-C₂ alkylene group is optionally substituted with oxo; and

-   R¹⁴ is hydrogen, C₁-C₆ alkyl, 5-10-membered monocyclic or bicyclic     heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆     alkyl, aryl or heteroaryl is optionally independently substituted     with 1, 2, or 3 R⁶; -   or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound of Formula AA

-   wherein -   m=0, 1, or 2; -   n=0, 1, or 2; -   o=1 or 2; -   p=0, 1, 2, or 3; -   wherein -   A is a 5-10-membered heteroaryl or a C₆-C₁₀ aryl; -   B is a 5-10-membered heteroaryl or a C₆-C₁₀ aryl; -   wherein -   at least one R⁶ is ortho to the bond connecting the B ring to the     NR³(CO) group of Formula AA; -   R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO—C₆-C₁₀ aryl, CO-(5- to 10-membered heteroaryl), CO₂C₁-C₆     alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5-     to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl,     N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to     10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl),     NHCOC₂-C₆ alkynyl, NHCOOC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹,     SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl,     C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl, -   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, and 3-     to 7-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy         substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²         3- to 7-membered heterocycloalkyl is further optionally         independently substituted with one to three hydroxy, halo,         NR⁸R⁹, or oxo;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or at least one pair of R¹ and R² on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5- to-8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆     alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹,     wherein the C₁-C₆ alkyl and C₁-C₆ alkoxy are optionally substituted     with hydroxy, halo, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl,     and CONR⁸R⁹; -   R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl,     OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to     7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅,     SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 3- to 10-membered     heterocycloalkyl, and C₂-C₆ alkenyl, -   wherein R⁶ and R⁷ are each optionally substituted with one or more     substituents independently selected from hydroxy, halo, CN, oxo,     C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3-     to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered     heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆     alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3-     to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy,     and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy     that R⁶ or R⁷ is substituted with is optionally substituted with one     or more hydroxyl, halo, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is     optionally fused to a five- to -seven-membered carbocyclic ring or     heterocyclic ring containing one or two heteroatoms independently     selected from oxygen, sulfur and nitrogen and optionally substituted     with halo;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5-to 8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹; -   R¹⁰ is C₁-C₆ alkyl; -   each of R⁸ and R⁹ at each occurrence is independently selected from     hydrogen, C₁-C₆ alkyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl,     S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl     is optionally substituted with one or more hydroxy, halo, C₁-C₆     alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl     or 3- to 7-membered heterocycloalkyl; or -   R⁸ and R⁹ taken together with the nitrogen they are attached to form     a 3- to 7-membered ring optionally containing one or more     heteroatoms in addition to the nitrogen they are attached to; -   R¹³ is C₁-C₆ alkyl, C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl; -   each of R¹¹ and R¹² at each occurrence is independently selected     from hydrogen and C₁-C₆ alkyl; -   R³ is selected from hydrogen, cyano, hydroxy, C₁-C₆ alkoxy, C₁-C₆     alkyl, CO₂C₁-C₆ alkyl, and

wherein the C₁-C₂ alkylene group is optionally substituted with oxo; and

-   R¹⁴ is hydrogen, C₁-C₆ alkyl, 5-10-membered monocyclic or bicyclic     heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆     alkyl, aryl or heteroaryl is optionally independently substituted     with 1, 2, or 3 R⁶; -   or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound of Formula AA

-   wherein -   m=0, 1, or 2; -   n=0, 1, or 2; -   o=1 or 2; -   p=0, 1, 2, or 3; -   wherein -   A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a     C₆-C₁₀ monocyclic or bicyclic aryl; -   B is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a     C₆-C₁₀ monocyclic or bicyclic aryl; -   wherein -   at least one R⁶ is ortho to the bond connecting the B ring to the     NR³(CO) group of Formula AA; -   R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO—C₆-C₁₀ aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆     alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5-     to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl,     N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to     10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl),     NHCOC₂-C₆ alkynyl, NHCOOCC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹,     SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl,     C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl, -   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to     7-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy         substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²         3- to 7-membered heterocycloalkyl is further optionally         independently substituted with one to three hydroxy, halo,         NR⁸R⁹, or oxo; wherein the 3- to 7-membered heterocycloalkyl,         C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl,         NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or at least one pair of R¹ and R² on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5- to-8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆     alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹,     wherein the C₁-C₆ alkyl and C₁-C₆ alkoxy are optionally substituted     with hydroxy, halo, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl,     and CONR⁸R⁹; -   R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl,     OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to     7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅,     SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl and 3- to     10-membered heterocycloalkyl, and C₂-C₆ alkenyl, -   wherein R⁶ and R⁷ are each optionally substituted with one or more     substituents independently selected from hydroxy, halo, CN, oxo,     C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3-     to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered     heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆     alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3-     to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy,     and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy     that R⁶ or R⁷ is substituted with is optionally substituted with one     or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is     optionally fused to a five- to -seven-membered carbocyclic ring or     heterocyclic ring containing one or two heteroatoms independently     selected from oxygen, sulfur and nitrogen;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹; -   R¹⁰ is C₁-C₆ alkyl; -   each of R⁸ and R⁹ at each occurrence is independently selected from     hydrogen, C₁-C₆ alkyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl,     S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl     is optionally substituted with one or more hydroxy, halo, C₁-C₆     alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl     or 3- to 7-membered heterocycloalkyl; or -   R⁸ and R⁹ taken together with the nitrogen they are attached to form     a 3- to 7-membered ring optionally containing one or more     heteroatoms in addition to the nitrogen they are attached to; -   R¹³ is C₁-C₆ alkyl, C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl; -   each of R¹¹ and R¹² at each occurrence is independently selected     from hydrogen and C₁-C₆ alkyl; and -   R³ is selected from hydrogen, cyano, hydroxy, C₁-C₆ alkoxy, C₁-C₆     alkyl, and

wherein the C₁-C₂ alkylene group is optionally substituted with oxo;

-   R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or     bicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein     each C₁-C₆ alkyl, aryl or heteroaryl is optionally independently     substituted with 1 or 2 R⁶; -   or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound of Formula AA

-   wherein -   m=0, 1, or 2; -   n=0, 1, or 2; -   o=1 or 2; -   p=0, 1, 2, or 3, -   wherein -   A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a     C₆-C₁₀ monocyclic or bicyclic aryl; -   B is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a     C₆-C₁₀ monocyclic or bicyclic aryl; -   wherein -   at least one R⁶ is ortho to the bond connecting the B ring to the     NH(CO) group of Formula AA; -   R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl); CO₂C₁-C₆     alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5-     to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl,     N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to     10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl),     NHCOC₂-C₆ alkynyl, NHCOOCC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹,     SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹²,     C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl, -   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to     7-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy         substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²         3- to 7-membered heterocycloalkyl is further optionally         independently substituted with one to three hydroxy, halo,         NR⁸R⁹, or oxo;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or at least one pair of R¹ and R² on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆     alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹     wherein the C₁-C₆ alkyl and C₁-C₆ alkoxy are optionally substituted     with hydroxy, halo, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl,     and CONR⁸R⁹; -   R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl,     OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to     7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅,     S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl and 3- to 10-membered     heterocycloalkyl, and a C₂-C₆ alkenyl, -   wherein R⁶ and R⁷ are each optionally substituted with one or more     substituents independently selected from hydroxy, halo, CN, oxo,     C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3-     to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered     heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆     alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3-     to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy,     and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy     that R⁶ or R⁷ is substituted with is optionally substituted with one     or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is     optionally fused to a five- to -seven-membered carbocyclic ring or     heterocyclic ring containing one or two heteroatoms independently     selected from oxygen, sulfur and nitrogen;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹; -   each of R⁴ and R⁵ is independently selected from hydrogen and C₁-C₆     alkyl; -   R¹⁰ is C₁-C₆ alkyl; -   each of R⁸ and R⁹ at each occurrence is independently selected from     hydrogen, C₁-C₆ alkyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl,     S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl     is optionally substituted with one or more hydroxy, halo, C₁-C₆     alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl     or 3- to 7-membered heterocycloalkyl; or -   R⁸ and R⁹ taken together with the nitrogen they are attached to form     a 3- to 7-membered ring optionally containing one or more     heteroatoms in addition to the nitrogen they are attached to; -   R¹³ is C₁-C₆ alkyl, C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl; -   each of R¹¹ and R¹² at each occurrence is independently selected     from hydrogen and C₁-C₆ alkyl; -   R³ is selected from hydrogen, cyano, hydroxy, C₁-C₆ alkoxy, C₁-C₆     alkyl, and

wherein the C₁-C₂ alkylene group is optionally substituted by oxo;

-   R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or     bicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein     each C₁-C₆ alkyl, aryl or heteroaryl is optionally independently     substituted with 1 or 2 R⁶; -   with the proviso that the compound of Formula AA is not a compound     selected from the group consisting of:

-   or a pharmaceutically acceptable salt thereof. -   In some embodiments, provided herein is a compound of Formula AA

-   wherein -   m=0, 1, or 2; -   n=0, 1, or 2; -   o=1 or 2; -   p=0, 1, 2, or 3, -   wherein -   A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a     C₆-C₁₀ monocyclic or bicyclic aryl; -   B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic     heteroaryl, or a C₆-C₁₀ monocyclic or bicyclic aryl; -   wherein -   at least one R⁶ is ortho to the bond connecting the B ring to the     NH(CO) group of Formula AA; -   R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl); CO₂C₁-C₆     alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5-     to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl,     N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to     10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl),     NHCOC₂-C₆ alkynyl, NHCOOCC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹,     SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹²,     C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl, -   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to     7-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy         substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²         3- to 7-membered heterocycloalkyl is further optionally         independently substituted with one to three hydroxy, halo,         NR⁸R⁹, or oxo;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or at least one pair of R¹ and R² on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆     alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹     wherein the C₁-C₆ alkyl and C₁-C₆ alkoxy are optionally substituted     with hydroxy, halo, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl,     and CONR⁸R⁹; -   R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl,     OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to     7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅,     S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl and 3- to 10-membered     heterocycloalkyl, and a C₂-C₆ alkenyl, -   wherein R⁶ and R⁷ are each optionally substituted with one or more     substituents independently selected from hydroxy, halo, CN, oxo,     C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3-     to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered     heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆     alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3-     to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy,     and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy     that R⁶ or R⁷ is substituted with is optionally substituted with one     or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is     optionally fused to a five- to -seven-membered carbocyclic ring or     heterocyclic ring containing one or two heteroatoms independently     selected from oxygen, sulfur and nitrogen;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹; -   each of R⁴ and R⁵ is independently selected from hydrogen and C₁-C₆     alkyl; -   R¹⁰ is C₁-C₆ alkyl; -   each of R⁸ and R⁹ at each occurrence is independently selected from     hydrogen, C₁-C₆ alkyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl,     S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl     is optionally substituted with one or more hydroxy, halo, C₁-C₆     alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl     or 3- to 7-membered heterocycloalkyl; or -   R⁸ and R⁹ taken together with the nitrogen they are attached to form     a 3- to 7-membered ring optionally containing one or more     heteroatoms in addition to the nitrogen they are attached to; -   R¹³ is C₁-C₆ alkyl, C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl; -   each of R¹¹ and R¹² at each occurrence is independently selected     from hydrogen and C₁-C₆ alkyl; -   R³ is selected from hydrogen, cyano, hydroxy, C₁-C₆ alkoxy, C₁-C₆     alkyl, and

wherein the C₁-C₂ alkylene group is optionally substituted by oxo; and

-   R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or     bicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein     each C₁-C₆ alkyl, aryl or heteroaryl is optionally independently     substituted with 1 or 2 R⁶; -   or a pharmaceutically acceptable salt thereof.

In certain of any of the foregoing embodiments, R³ is H or methyl, wherein the compound is other than:

In some embodiments, provided herein is a compound of Formula AA:

wherein the

moiety is as defined for (AA-1), (AA-2), (AA-3), or (AA-4) below:

(AA-1):

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₇-C₁₀ bicyclic aryl;

m=0, 1, or 2; and

n=0, 1, or 2;

(AA-2):

A is phenyl;

m=0, 1, or 2; and

n=0, 1, or 2, provided that m+n=0, 2, 3, or 4;

(AA-3):

(AA-4):

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C₆-C₁₀ monocyclic or bicyclic aryl; wherein at least one R⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA;

o=1 or 2;

p=0, 1, 2, or 3;

when (AA-1), (AA-2), or (AA-3) applies,

R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NR⁸R⁹, C(O)R¹³, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl,

wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);

wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃ alkylene)C₆-C₁₀ aryl, halo, NR⁸R⁹, or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

or one pair of R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹,

wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

OR

when (AA-4) applies, R¹′ is selected from the group consisting of:

methyl; C₂-C₆ alkyl; C₁-C₆ haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂; CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀ aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl; NR⁸R⁹; C(O)R¹³; CONR⁸R⁹; SF₅; SC₁-C₆ alkyl; S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl; S(O₂)NR¹¹R¹²; C₃-C₇ cycloalkyl; and 3- to 7-membered heterocycloalkyl,

wherein when R¹′ is methyl, R¹′ is substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl); and

when R¹′ is selected from the group consisting of C₂-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl, R¹′ is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);

wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R^(1′) C₃-C₇ cycloalkyl or of the R^(1′) 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, —O(C₀-C₃ alkylene)C₆-C₁₀ aryl, NR⁸R⁹, or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl,

wherein R⁶ and R⁷ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy that R⁶ or R⁷ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

R¹⁰ is C₁-C₆ alkyl;

each of R⁸ and R⁹ at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR¹¹R¹²;

or R⁸ and R⁹ taken together with the nitrogen they are attached to form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

R¹³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, or —(Z¹—Z²)_(a1)—Z³;

each of R¹¹ and R¹² at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, and —(Z¹—Z²)_(a1)—Z³;

a1 is 0-10 (e.g., 0-4);

each Z¹ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy;

each Z² is independently a bond, NH, N(C₁-C₆ alkyl), —O—, —S—, or 5-10 membered heteroarylene;

Z³ is independently C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

R³ is selected from hydrogen and C₁-C₆ alkyl (e.g., R³ is selected from hydrogen and methyl);

R¹⁵ is —(Z⁴—Z⁵)_(a2)—Z⁶;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z⁴ is independently selected from —O—, —S—, —NH—, and —N(C₁-C₃ alkyl)-;

provided that the Z⁴ group directly attached to R¹ or R² is —O— or —S—;

each Z⁵ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z⁶ is OH, OC₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, NHC(O)(C₁-C₆ alkyl), NHC(O)(C₁-C₆ alkoxy), or an optionally substituted group selected from the group consisting of:

C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆ alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound of Formula AA

wherein the

moiety is as defined for (AA-1), (AA-2), (AA-3), or (AA-4) below:

(AA-1):

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₇-C₁₀ bicyclic aryl;

m=0, 1, or 2; and

n=0, 1, or 2;

(AA-2):

A is phenyl;

m=0, 1, or 2; and

n=0, 1, or 2, provided that m+n=0, 2, 3, or 4;

(AA-3):

(AA-4):

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C₆-C₁₀ monocyclic or bicyclic aryl; wherein at least one R⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA;

o=1 or 2;

p=0, 1, 2, or 3;

when (AA-1), (AA-2), or (AA-3) apply,

R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO—C₆-C₁₀ aryl, CO(5- to 10-membered heteroaryl); CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, NHCOOCC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl,

wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl;

wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃ alkylene)C₆-C₁₀ aryl, halo, NR⁸R⁹, or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

or one pair of R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹,

wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

OR

when (AA-4) applies, R¹′ is selected from the group consisting of:

methyl; C₂-C₆ alkyl; C₁-C₆ haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂; COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀ aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; NHCOC₁-C₆ alkyl; NHCOC₆-C₁₀ aryl; NHCO(5- to 10-membered heteroaryl); NHCO(3- to 7-membered heterocycloalkyl); NHCOC₂-C₆ alkynyl; NHCOOC₁-C₆ alkyl; NH—(C═NR¹³)NR¹¹R¹²; CONR⁸R⁹; SF₅; SC₁-C₆ alkyl; S(O₂)C₁-C₆ alkyl; S(O)C₁-C₆ alkyl; S(O₂)NR¹¹R¹²; C₃-C₇ cycloalkyl; and 3- to 7-membered heterocycloalkyl,

wherein when R¹′ is methyl, R¹′ is substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);

wherein when R¹′ is selected from the group consisting of C₂-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl, R¹′ is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl;

wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R^(1′) C₃-C₇ cycloalkyl or of the R¹′ 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃ alkylene)C₆-C₁₀ aryl, halo, NR⁸R⁹, or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl,

wherein R⁶ and R⁷ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy that R⁶ or R⁷ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

R¹⁰ is C₁-C₆ alkyl;

each of R⁸ and R⁹ at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR¹¹R¹²; or R⁸ and R⁹ taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to;

R¹³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl; each of R¹¹ and R¹² at each occurrence is independently selected from hydrogen and C₁-C₆ alkyl;

R³ is selected from hydrogen and C₁-C₆ alkyl (e.g., R³ is selected from hydrogen and methyl);

R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆ alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R⁶;

R¹⁵ is —(Z⁴—Z⁵)_(a2)—Z⁶;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z⁴ is independently selected from —O—, —S—, —NH—, and —N(C₁-C₃ alkyl)-;

provided that the Z⁴ group directly attached to R¹ or R² is —O— or —S—;

each Z⁵ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z⁶ is OH, OC₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, NHC(O)(C₁-C₆ alkyl), NHC(O)(C₁-C₆ alkoxy), or an optionally substituted group selected from the group consisting of:

C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound of Formula AA

wherein

m=1 or 2;

n=1 or 2;

o=1 or 2;

p=0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₆-C₁₀ monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C₆-C₁₀ monocyclic or bicyclic aryl; wherein at least one R⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA;

one pair of R¹ and R² are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹,

wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

each of R¹ and R² that are not taken together with the atoms connecting them to form at least one ring is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NR⁸R⁹, C(O)R¹³, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl,

wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);

wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃ alkylene)C₆-C₁₀ aryl, halo, NR⁸R⁹, or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl,

wherein R⁶ and R⁷ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy that R⁶ or R⁷ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

R¹⁰ is C₁-C₆ alkyl;

each of R⁸ and R⁹ at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR¹¹R¹²;

or R⁸ and R⁹ taken together with the nitrogen they are attached to form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

R¹³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, or —(Z¹—Z²)_(a1)—Z³;

each of R¹¹ and R¹² at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, and —(Z¹—Z²)_(a1)—Z³;

a1 is 0-10 (e.g., 0-4);

each Z¹ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy;

each Z² is independently a bond, NH, N(C₁-C₆ alkyl), —O—, —S—, or 5-10 membered heteroarylene;

Z³ is independently C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

R³ is selected from hydrogen, cyano, hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkyl, and

wherein the C₁-C₂ alkylene group is optionally substituted by oxo;

R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆ alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R⁶,

R¹⁵ is —(Z⁴—Z⁵)_(a2)—Z⁶;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z⁴ is independently selected from —O—, —S—, —NH—, and —N(C₁-C₃ alkyl)-;

provided that the Z⁴ group directly attached to R¹ or R² is —O— or —S—;

each Z⁵ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z⁶ is OH, OC₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, NHC(O)(C₁-C₆ alkyl), NHC(O)(C₁-C₆ alkoxy), or an optionally substituted group selected from the group consisting of:

C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound of Formula AA

wherein

m=1 or 2;

n=1 or 2;

o=1 or 2;

p=0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₆-C₁₀ monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C₆-C₁₀ monocyclic or bicyclic aryl; wherein at least one R⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA;

one pair of R¹ and R² are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹,

wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

each of R¹ and R² that are not taken together with the atoms connecting them to form at least one ring is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NR⁸R⁹, C(O)R¹³, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl,

wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);

wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃ alkylene)C₆-C₁₀ aryl, halo, NR⁸R⁹, or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl,

wherein R⁶ and R⁷ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy that R⁶ or R⁷ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

R¹⁰ is C₁-C₆ alkyl;

each of R⁸ and R⁹ at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR¹¹R¹²;

or R⁸ and R⁹ taken together with the nitrogen they are attached to form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

R¹³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, or —(Z¹—Z²)_(a1)—Z³;

each of R¹¹ and R¹² at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, and —(Z¹—Z²)_(a1)—Z³;

a1 is 0-10 (e.g., 0-4);

each Z¹ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy;

each Z² is independently a bond, NH, N(C₁-C₆ alkyl), —O—, —S—, or 5-10 membered heteroarylene;

Z³ is independently C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

R³ is selected from hydrogen and C₁-C₆ alkyl (e.g., R³ is selected from hydrogen and methyl);

R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆ alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R⁶,

R¹⁵ is —(Z⁴—Z⁵)_(a2)—Z⁶;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z⁴ is independently selected from —O—, —S—, —NH—, and —N(C₁-C₃ alkyl)-;

provided that the Z⁴ group directly attached to R¹ or R² is —O— or —S—;

each Z⁵ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z⁶ is OH, OC₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, NHC(O)(C₁-C₆ alkyl), NHC(O)(C₁-C₆ alkoxy), or an optionally substituted group selected from the group consisting of:

C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆ alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound of Formula AA

wherein

m=1 or 2;

n=1 or 2;

o=1 or 2;

p=0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₆-C₁₀ monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C₆-C₁₀ monocyclic or bicyclic aryl;

wherein at least one R⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA;

one pair of R¹ and R² are on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹,

wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

each of R¹ and R² that are not taken together with the atoms connecting them to form at least one ring is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO—C₆-C₁₀ aryl, CO(5- to 10-membered heteroaryl); CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, NHCOOCC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl,

wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl;

wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃ alkylene)C₆-C₁₀ aryl, halo, NR⁸R⁹, or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl,

wherein R⁶ and R⁷ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy that R⁶ or R⁷ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

R¹⁰ is C₁-C₆ alkyl;

each of R⁸ and R⁹ at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR¹¹R¹²; or R⁸ and R⁹ taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to;

R¹³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl;

each of R¹¹ and R¹² at each occurrence is independently selected from hydrogen and C₁-C₆ alkyl;

R³ is selected from hydrogen, cyano, hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkyl, and

wherein the C₁-C₂ alkylene group is optionally substituted by oxo;

R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆ alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R⁶,

R¹⁵ is —(Z⁴—Z⁵)_(a2)—Z⁶;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z⁴ is independently selected from —O—, —S—, —NH—, and —N(C₁-C₃ alkyl)-;

provided that the Z⁴ group directly attached to R¹ or R² is —O— or —S—;

each Z⁵ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z⁶ is OH, OC₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, NHC(O)(C₁-C₆ alkyl), NHC(O)(C₁-C₆ alkoxy), or an optionally substituted group selected from the group consisting of:

C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆ alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound of Formula AA

wherein

m=1 or 2;

n=1 or 2;

o=1 or 2;

p=0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₆-C₁₀ monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C₆-C₁₀ monocyclic or bicyclic aryl;

wherein at least one R⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA;

one pair of R¹ and R² are on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹,

wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

each of R¹ and R² that are not taken together with the atoms connecting them to form at least one ring is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO—C₆-C₁₀ aryl, CO(5- to 10-membered heteroaryl); CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, NHCOOCC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl,

wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl;

wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃ alkylene)C₆-C₁₀ aryl, halo, NR⁸R⁹, or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl,

wherein R⁶ and R⁷ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy that R⁶ or R⁷ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

R¹⁰ is C₁-C₆ alkyl;

each of R⁸ and R⁹ at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR¹¹R¹²; or R⁸ and R⁹ taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to;

R¹³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl;

each of R¹¹ and R¹² at each occurrence is independently selected from hydrogen and C₁-C₆ alkyl;

R³ is selected from hydrogen and C₁-C₆ alkyl (e.g., R³ is selected from hydrogen and methyl);

R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆ alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R⁶,

R¹⁵ is —(Z⁴—Z⁵)_(a2)—Z⁶;

a2 is an integer selected from 1-10 (e.g., 1-5);

each Z⁴ is independently selected from —O—, —S—, —NH—, and —N(C₁-C₃ alkyl)-;

provided that the Z⁴ group directly attached to R¹ or R² is —O— or —S—;

each Z⁵ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z⁶ is OH, OC₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, NHC(O)(C₁-C₆ alkyl), NHC(O)(C₁-C₆ alkoxy), or an optionally substituted group selected from the group consisting of:

C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound of Formula AA

wherein

m=1 or 2;

n=1 or 2;

o=1 or 2;

p=0, 1, 2, or 3,

wherein

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₆-C₁₀ monocyclic or bicyclic aryl;

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C₆-C₁₀ monocyclic or bicyclic aryl;

wherein at least one R⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA;

one pair of R¹ and R² are on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹,

wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

each of R¹ and R² that are not taken together with the atoms connecting them to form at least one ring is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO—C₆-C₁₀ aryl, CO(5- to 10-membered heteroaryl); CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, NHCOOCC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl,

wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl;

wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR⁸R⁹, or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl,

wherein R⁶ and R⁷ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy that R⁶ or R⁷ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

each of R⁴ and R⁵ is independently selected from hydrogen and C₁-C₆ alkyl;

R¹⁰ is C₁-C₆ alkyl;

each of R⁸ and R⁹ at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl, or 3- to 7-membered heterocycloalkyl; or

-   R⁸ and R⁹ taken together with the nitrogen they are attached to form     a 3- to 7-membered ring optionally containing one or more     heteroatoms in addition to the nitrogen they are attached to; -   R¹³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, or 5- to     10-membered heteroaryl; -   each of R¹¹ and R¹² at each occurrence is independently selected     from hydrogen and C₁-C₆ alkyl;

R³ is selected from hydrogen, cyano, hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkyl, and

wherein the C₁-C₂ alkylene group is optionally substituted by oxo; and

R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆ alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R⁶,

or a pharmaceutically acceptable salt thereof.

In certain of any of the foregoing embodiments, it is provided that the compound is not selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula AA is other than one of the following compounds:

In some embodiments the variables shown in the formulae herein are as follows:

The

moiety

-   In some embodiments, the

is as defined for (AA-1):

A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₇-C₁₀ bicyclic aryl;

m=0, 1, or 2; and

n=0, 1, or 2.

-   In some embodiments, the

is as defined for (AA-2):

A is phenyl;

m=0, 1, or 2; and

n=0, 1, or 2, provided that m+n=0, 2, 3, or 4.

-   In some embodiments, the

moiety is

-   In some embodiments, the

moiety is

The Variables m and n

-   In some embodiments m=0, 1, or 2. -   In some embodiments m=0 or 1. -   In some embodiments m=1 or 2. -   In some embodiments m=0 or 2. -   In some embodiments m=0. -   In some embodiments m=1. -   In some embodiments m=2. -   In some embodiments n=0, 1, or 2. -   In some embodiments n=0 or 1. -   In some embodiments n=1 or 2. -   In some embodiments n=0 or 2. -   In some embodiments n=0. -   In some embodiments n=1. -   In some embodiments n=2. -   In some embodiments, m=0, and n=0. -   In some embodiments, m=1, and n=0. -   In some embodiments, m=1, and n=1.

The Ring A and Substitutions on the Ring A

-   In some embodiments, A is a 5- to 10-membered (e.g., 5- to     6-membered) monocyclic or bicyclic heteroaryl or a C₆-C₁₀ (e.g., C₆)     monocyclic or bicyclic aryl, such as phenyl. -   In some embodiments, A is a 5- to 10-membered (e.g., 5- to     6-membered) monocyclic or bicyclic heteroaryl. -   In some embodiments, A is a 5-membered heteroaryl. -   In some embodiments, A is a 5-membered heteroaryl containing a     sulfur and optionally one or more nitrogens. -   In some embodiments, A is a 6-membered heteroaryl. -   In some embodiments, A is a C₆-C₁₀ monocyclic or bicyclic aryl. -   In some embodiments, A is phenyl optionally substituted with 1 or 2     R¹ and optionally substituted with 1 or 2 R². -   In some embodiments, A is naphthyl optionally substituted with 1 or     2 R¹ and optionally substituted with 1 or 2 R². -   In some embodiments, A is furanyl optionally substituted with 1 or 2     R¹ and optionally substituted with 1 R². -   In some embodiments, A is furanyl optionally substituted with 1 R¹     and optionally substituted with 1 or 2R². -   In some embodiments, A is thiophenyl optionally substituted with 1     or 2 R¹ and optionally substituted with 1 or 2 R². -   In some embodiments, A is oxazolyl optionally substituted with 1 or     2 R¹ and optionally substituted with 1 or 2 R². -   In some embodiments, A is thiazolyl optionally substituted with 1 or     2 R¹ and optionally substituted with 1 or 2 R². -   In some embodiments, A is oxazolyl optionally substituted with 2 R¹     or optionally substituted with 2 R². -   In some embodiments, A is thiazolyl optionally substituted with 2 R¹     or optionally substituted with 2 R². -   In some embodiments, A is pyrazolyl optionally substituted with 1 or     2 R¹ and optionally substituted with 1 or 2 R². -   In some embodiments, A is pyrazolyl optionally substituted with 1 R¹     and optionally substituted with 1 or 2 R². -   In some embodiments, A is pyrazolyl optionally substituted with 1 or     2 R¹ and optionally substituted with 1 R². -   In some embodiments, A is imidazolyl optionally substituted with 1     or 2 R¹ and optionally substituted with 1 or 2 R². -   In some embodiments, A is pyrrolyl optionally substituted with 1 or     2 R¹ and optionally substituted with 1 or 2 R². -   In some embodiments, A is oxazolyl optionally substituted with 1 or     2 R¹ and optionally substituted with 1 or 2 R². -   In some embodiments, A is furanyl optionally substituted with 1 or 2     R¹ and optionally substituted with 1 or 2 R². -   In some embodiments, A is isoxazolyl optionally substituted with 1     or 2 R¹ and optionally substituted with 1 or 2 R². -   In some embodiments, A is isothiazolyl optionally substituted with 1     or 2 R¹ and optionally substituted with 1 or 2 R². -   In some embodiments, A is triazolyl (e.g., 1,2,3-triazolyl or     1,2,4-triazolyl) optionally substituted with 1 R¹ and optionally     substituted with 1 R². -   In some embodiments, A is pyridyl optionally substituted with 1 or 2     R¹ and optionally substituted with 1 or 2 R². -   In some embodiments, A is pyridinyl optionally substituted with 1 or     2 R¹ and optionally substituted with 1 or 2 R². -   In some embodiments, A is pyridimidinyl optionally substituted with     1 or 2 R¹ and optionally substituted with 1 or 2 R². -   In some embodiments, A is pyrazinyl optionally substituted with 1 or     2 R¹ and optionally substituted with 1 or 2 R². -   In some embodiments, A is pyridazinyl optionally substituted with 1     or 2 R¹ and optionally substituted with 1 or 2 R². -   In some embodiments, A is triazinyl optionally substituted with 1 or     2 R¹ and optionally substituted with 1 or 2 R². -   In some embodiments, A is indazolyl optionally substituted with 1 or     2 R¹ and optionally substituted with 1 or 2 R². -   In some embodiments, A is phenyl substituted with 1 R¹ and     optionally substituted with 1 R². -   In some embodiments, A is naphthyl substituted with 1 R¹ and     optionally substituted with 1 R². -   In some embodiments, A is furanyl substituted with 1 R¹ and     optionally substituted with 1 R². -   In some embodiments, A is thiophenyl substituted with 1 R¹ and     optionally substituted with 1 R². -   In some embodiments, A is oxazolyl substituted with 1 R¹ and     optionally substituted with 1 R². -   In some embodiments, A is thiazolyl substituted with 1 R¹ and     optionally substituted with 1 R². -   In some embodiments, A is pyrazolyl substituted with 1 R¹ and     optionally substituted with 1 R². -   In some embodiments, A is imidazolyl substituted with 1 R¹ and     substituted with 1 R². -   In some embodiments, A is pyrrolyl substituted with 1 R¹ and     substituted with 1 R². -   In some embodiments, A is oxazolyl substituted with 1 R¹ and     substituted with 1 R². -   In some embodiments, A is furanyl substituted with 1 R¹ and     substituted with 1 R². -   In some embodiments, A is isoxazolyl substituted with 1 R¹ and     substituted with 1 R². -   In some embodiments, A is isothiazolyl substituted with 1 R¹ and     substituted with 1 R². -   In some embodiments, A is triazolyl (e.g., 1,2,3-triazolyl or     1,2,4-triazolyl) substituted with 1 R¹ and substituted with 1 R². -   In some embodiments, A is pyridyl substituted with 1 R¹ and     optionally substituted with 1 R². -   In some embodiments, A is pyridimidinyl substituted with 1 R¹ and     substituted with 1 R². -   In some embodiments, A is pyrazinyl substituted with 1 R¹ and     substituted with 1 R². -   In some embodiments, A is pyridazinyl substituted with 1 R¹ and     substituted with 1 R². -   In some embodiments, A is triazinyl substituted with 1 R¹ and     substituted with 1 R². -   In some embodiments, A is indazolyl optionally substituted with 1 R¹     and optionally substituted with 1 R². -   In some embodiments, A is phenyl substituted with 1 R¹ and     substituted with 1 R². -   In some embodiments, A is furanyl substituted with 1 R¹ and     substituted with 1 R². -   In some embodiments, A is thiophenyl substituted with 1 R¹ and     substituted with 1 R². -   In some embodiments, A is oxazolyl substituted with 1 R¹ and     substituted with 1 R². -   In some embodiments, A is thiazolyl substituted with 1 R¹ and     substituted with 1 R². -   In some embodiments, A is pyrazolyl substituted with 1 R¹ and     substituted with 1 R². -   In some embodiments, A is pyridyl substituted with 1 R¹ and     substituted with 1 R². -   In some embodiments, A is pyridazinyl substituted with 1 R¹ and     substituted with 1 R². -   In some embodiments, A is phenyl, m is 0 or 1, and n is 0, 1, or 2. -   In some embodiments, A is furanyl, m is 0 or 1, and n is 0, 1, or 2. -   In some embodiments, A is thiophenyl, m is 0 or 1, and n is 0, 1, or     2. -   In some embodiments, A is oxazolyl, m is 0 or 1, and n is 0, 1, or     2. -   In some embodiments, A is thiazolyl, m is 0 or 1, and n is 0, 1, or     2. -   In some embodiments, A is pyrazolyl, m is 0 or 1, and n is 0, 1, or     2. -   In some embodiments, A is pyridyl, m is 0 or 1, and n is 0, 1, or 2. -   In some embodiments, A is pyridazinyl, m is 0 or 1, and n is 0, 1,     or 2. -   In some embodiments, A is indazolyl, m is 0 or 1, and n is 0, 1, or     2. -   In some embodiments, A is phenyl, m is 0, and n is 0 or 1. -   In some embodiments, A is furanyl, m is 0, and n is 0 or 1. -   In some embodiments, A is thiophenyl, m is 0, and n is 0 or 1. -   In some embodiments, A is oxazolyl, m is 0, and n is 0 or 1. -   In some embodiments, A is thiazolyl, m is 0, and n is 0 or 1. -   In some embodiments, A is pyrazolyl, m is 0, and n is 0 or 1. -   In some embodiments, A is pyridyl, m is 0, and n is 0 or 1. -   In some embodiments, A is thiazolyl, m is 1, and n is 1. -   In some embodiments, A is pyrazolyl, m is 1 or 2, and n is 1 or 2. -   In some embodiments, A is imidazolyl, m is 1 or 2, and n is 1 or 2. -   In some embodiments, A is pyrrolyl, m is 1 or 2, and n is 1 or 2. -   In some embodiments, A is oxazolyl, m is 1, and n is 1. -   In some embodiments, A is furanyl, m is 1 or 2, and n is 1 or 2. -   In some embodiments, A is isoxazolyl, m is 1, and n is 1. -   In some embodiments, A is isothiazolyl, m is 1, and n is 1. -   In some embodiments, A is triazolyl (e.g., 1,2,3-triazolyl or     1,2,4-triazolyl), m is 1, and n is 1. -   In some embodiments, A is pyridinyl, m is 1 or 2, and n is 1 or 2. -   In some embodiments, A is pyridimidinyl, m is 1 or 2, and n is 1 or     2. -   In some embodiments, A is pyrazinyl, m is 1 or 2, and n is 1 or 2. -   In some embodiments, A is pyridazinyl, m is 1 or 2, and n is 1 or 2. -   In some embodiments, A is triazinyl, m is 1, and n is 1. -   In some embodiments, A is one of the rings disclosed hereinbelow     optionally substituted as disclosed hereinbelow, wherein in each     case the bond that is shown as being broken by the wavy line     connects A to the S(O)(NR³R³)═N moiety of Formula AA.     In some embodiments, the optionally substituted ring A

In some embodiments, the optionally substituted ring A is

In some embodiments, the optionally substituted ring A is

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In some embodiments, the optionally substituted ring A is

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In some embodiments, the optionally substituted ring A is selected from the group consisting of:

In some embodiments, the optionally substituted ring A is selected from the group consisting of:

In some embodiments, the optionally substituted ring A is selected from the group consisting of:

In some embodiments, the optionally substituted ring A is selected from the group consisting of:

In some embodiments, the optionally substituted ring A is selected from the group consisting of:

In some embodiments, when ring A is phenyl, then R¹ and R² are each independently selected from C₃ alkyl, C₅-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, F, I, CN, NO₂, COC₂-C₆ alkyl, CO—C₆-C₁₀ aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₂-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, NHCOOCC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl, C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl;

-   -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy         substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²         3- to 7-membered heterocycloalkyl is further optionally         independently substituted with one to three hydroxy, halo,         NR⁸R⁹, or oxo;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl;

-   or one pair of R¹ and R² on adjacent atoms, taken together with the     atoms connecting them, independently form one monocyclic or bicyclic     C₄ or C₆-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5-     to-12-membered heterocyclic ring containing 1-3 heteroatoms     independently selected from O, N, and S, wherein the carbocyclic     ring or heterocyclic ring is optionally independently substituted     with one or more substituents each independently selected from     hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆     alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl,     OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl,     and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀     aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl,     and 3- to 10-membered heterocycloalkyl are optionally substituted     with one or more substituents each independently selected from     hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀     cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹.

-   In some embodiments, R¹ and R² are each independently selected from     C₃ alkyl, CS-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆     haloalkoxy, F, I, CN, NO₂, COC₂-C₆ alkyl, CO—C₆-C₁₀ aryl, CO(5- to     10-membered heteroaryl), CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl,     OCOC₂-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl),     OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆     alkynyl, NHCOOCC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆     alkyl, S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl, C₃-C₇     cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆     alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to 7-membered     heterocycloalkyl are optionally substituted with one or more     substituents each independently selected from hydroxy, halo, CN,     oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy         substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²         3- to 7-membered heterocycloalkyl is further optionally         independently substituted with one to three hydroxy, halo,         NR⁸R⁹, or oxo;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl;

-   or one pair of R¹ and R² on adjacent atoms, taken together with the     atoms connecting them, independently form one monocyclic or bicyclic     C₄ or C₆-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5-     to-12-membered heterocyclic ring containing 1-3 heteroatoms     independently selected from O, N, and S, wherein the carbocyclic     ring or heterocyclic ring is optionally independently substituted     with one or more substituents each independently selected from     hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆     alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl,     OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl,     and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀     aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl,     and 3- to 10-membered heterocycloalkyl are optionally substituted     with one or more substituents each independently selected from     hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀     cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹.

-   In some embodiments of the compound of Formula AA, when ring A is     pyridyl, then R¹ and R² are each independently selected from C₁-C₆     alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN,     NO₂, COC₁-C₆ alkyl, CO—C₆-C₁₀ aryl, CO(5- to 10-membered     heteroaryl), CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl,     OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to     7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, NH₂, NHC₂-C₆ alkyl, N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl,     NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to     7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, NHCOOCC₁-C₆ alkyl,     NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl,     S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl, C₃-C₇ cycloalkyl, and 3- to     7-membered heterocycloalkyl,

-   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, and 3-     to 7-membered heterocycloalkyl are optionally substituted with one     or more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 5-membered heterocycloalkyl, 5-membered heteroaryl,     OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl),     OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀     aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered     heterocycloalkyl), and NHCOC₂-C₆ alkynyl;     -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy         substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²         3- to 7-membered heterocycloalkyl is further optionally         independently substituted with one to three hydroxy, halo,         NR⁸R⁹, or oxo;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl;

-   or one pair of R¹ and R² on adjacent atoms, taken together with the     atoms connecting them, independently form one monocyclic or bicyclic     C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5-     to-12-membered heterocyclic ring containing 1-3 heteroatoms     independently selected from O, N, and S, wherein the carbocyclic     ring or heterocyclic ring is optionally independently substituted     with one or more substituents each independently selected from     hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆     alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl,     OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl,     and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀     aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl,     and 3- to 10-membered heterocycloalkyl are optionally substituted     with one or more substituents each independently selected from     hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀     cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹.

-   In some embodiments of the compound of Formula AA, R¹ and R² are     each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆     alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO—C₆-C₁₀     aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆ alkyl, CO₂C₃-C₈     cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered     heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5-     to 10-membered heteroaryl, NH₂, NHC₂-C₆ alkyl, N(C₁-C₆ alkyl)₂,     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆     alkynyl, NHCOOCC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆     alkyl, S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl, C₃-C₇     cycloalkyl, and 3- to 7-membered heterocycloalkyl,

-   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, and 3-     to 7-membered heterocycloalkyl are optionally substituted with one     or more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 5-membered heterocycloalkyl, 5-membered heteroaryl,     OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl),     OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀     aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered     heterocycloalkyl), and NHCOC₂-C₆ alkynyl;     -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy         substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²         3- to 7-membered heterocycloalkyl is further optionally         independently substituted with one to three hydroxy, halo,         NR⁸R⁹, or oxo;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl;

-   or one pair of R¹ and R² on adjacent atoms, taken together with the     atoms connecting them, independently form one monocyclic or bicyclic     C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5-     to-12-membered heterocyclic ring containing 1-3 heteroatoms     independently selected from O, N, and S, wherein the carbocyclic     ring or heterocyclic ring is optionally independently substituted     with one or more substituents each independently selected from     hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆     alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl,     OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl,     and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀     aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl,     and 3- to 10-membered heterocycloalkyl are optionally substituted     with one or more substituents each independently selected from     hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀     cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹.     The groups R¹ and R²

-   In some embodiments,

-   R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO—C₆-C₁₀ aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆     alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5-     to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl,     N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl,     S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered     heterocycloalkyl,

-   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to     7-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);     -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy         substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²         3- to 7-membered heterocycloalkyl is further optionally         independently substituted with one to three hydroxy, halo,         NR⁸R⁹, or oxo;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, and         5- to 10-membered heteroaryl are optionally substituted with one         or more substituents independently selected from halo, C₁-C₆         alkyl, and OC₁-C₆ alkyl;

-   or at least one pair of R¹ and R² on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5- to-8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆     alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

-   In some embodiments,

-   R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl); CO₂C₁-C₆     alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5-     to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl,     N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl,     S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered     heterocycloalkyl,

-   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to     7-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy         substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²         3- to 7-membered heterocycloalkyl is further optionally         independently substituted with one to three hydroxy, halo,         NR⁸R⁹, or oxo;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl;

-   or at least one pair of R¹ and R² on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆     alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

-   In some embodiments,

-   R¹ and R² are each independently selected from C₁-C₆ haloalkyl,     C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl,     CO—C₆-C₁₀ aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆ alkyl,     CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl,     N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl,     S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered     heterocycloalkyl, wherein the C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, and     3- to 7-membered heterocycloalkyl is optionally substituted with one     or more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy         substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²         3- to 7-membered heterocycloalkyl is further optionally         independently substituted with one to three hydroxy, halo,         NR⁸R⁹, or oxo;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl;

-   or at least one pair of R¹ and R² on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆     alkoxy, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

-   In some embodiments,

-   R¹ and R² are each independently selected from C₁-C₆ alkyl, halo,     CN, NO₂, COC₁-C₆ alkyl, CO—C₆-C₁₀ aryl, CO(5- to 10-membered     heteroaryl), CO₂C₁-C₆ alkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5-     to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl,     N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl,     S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered     heterocycloalkyl,

-   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to     7-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy         substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²         3- to 7-membered heterocycloalkyl is further optionally         independently substituted with one to three hydroxy, halo,         NR⁸R⁹, or oxo;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl;

-   or at least one pair of R¹ and R² on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆     alkoxy, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

-   In some embodiments,

-   R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO—C₆-C₁₀ aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆     alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5-     to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl,     N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl,     S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered     heterocycloalkyl,

-   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to     7-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy         substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²         3- to 7-membered heterocycloalkyl is further optionally         independently substituted with one to three hydroxy, halo, or         oxo;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl;

-   or at least one pair of R¹ and R² on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5- to-8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆     alkoxy, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

-   In some embodiments,

-   R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO—C₆-C₁₀ aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆     alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5-     to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl,     N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl,     S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered     heterocycloalkyl,

-   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to     7-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl.

-   In some embodiments,

-   R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO—C₆-C₁₀ aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆     alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5-     to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl,     N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl,     S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered     heterocycloalkyl,

-   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to     7-membered heterocycloalkyl are each unsubstituted;

-   or at least one pair of R¹ and R² on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5- to-8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆     alkoxy, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

-   In some embodiments,

-   R¹ and R² are each independently selected from C₁-C₆ alkyl, halo,     CN, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, C₆-C₁₀ aryl, S(O)C₁-C₆ alkyl, 5-     to 10-membered heteroaryl, and 3- to 7-membered heterocycloalkyl,

-   wherein the C₁-C₆ alkyl and 3- to 7-membered heterocycloalkyl is     optionally substituted with one or more substituents each     independently selected from hydroxy and oxo.

-   In some embodiments, m=1; n=0; and

-   R¹ is selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,     C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO—C₆-C₁₀ aryl,     CO(5- to 10-membered heteroaryl), CO₂C₁-C₆ alkyl, CO₂C₃-C₈     cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered     heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5-     to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,     CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹²,     S(O)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered     heterocycloalkyl,

-   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to     7-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl.

-   In some embodiments , m=1; n=0; and,

-   R¹ is selected from C₁-C₆ alkyl, halo, CN, COC₁-C₆ alkyl, CO₂C₁-C₆     alkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, S(O)C₁-C₆ alkyl,     and 3- to 7-membered heterocycloalkyl,

-   wherein the C₁-C₆ alkyl and 3- to 7-membered heterocycloalkyl is     optionally substituted with one or more substituents each     independently selected from hydroxy and oxo.

-   In some embodiments, m=1; n=1; and

-   R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO—C₆-C₁₀ aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆     alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5-     to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl,     N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl,     S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered     heterocycloalkyl,

-   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to     7-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;

-   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are     optionally substituted with one or more substituents independently     selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl;

-   In some embodiments , m=1; n=1; and,

-   R¹ and R² are each independently selected from C₁-C₆ alkyl, halo,     CN, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, S(O)C₁-C₆ alkyl, and 3- to 7-membered heterocycloalkyl,

-   wherein the C₁-C₆ alkyl and 3- to 7-membered heterocycloalkyl is     optionally substituted with one or more substituents each     independently selected from hydroxy and oxo.

-   In some embodiments, m=1; n=1; and

-   R¹ and R² are on adjacent atoms, and taken together with the atoms     connecting them, form a C₄-C₈ carbocyclic ring or a 5- to-8-membered     heterocyclic ring containing 1 or 2 heteroatoms independently     selected from O, N, and S, wherein the carbocyclic ring or     heterocyclic ring is optionally independently substituted with one     or more substituents independently selected from hydroxy, halo, oxo,     C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹.

-   In some embodiments, m=1; n=1; and

-   R¹ and R² are on adjacent atoms, and taken together with the atoms     connecting them, form a C₆ carbocyclic ring or a 5-to-6-membered     heterocyclic ring containing 1 or 2 heteroatoms independently     selected from O, N, and S, wherein the carbocyclic ring or     heterocyclic ring is optionally independently substituted with one     or more substituents independently selected from hydroxy, halo, oxo,     C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹.

-   In some embodiments, m=1; n=1; and

-   R¹ and R² are on adjacent atoms, and taken together with the atoms     connecting them, form a C₅ carbocyclic ring or a 5- to-6-membered     heterocyclic ring containing 1 or 2 heteroatoms independently     selected from O, N, and S, wherein the carbocyclic ring or     heterocyclic ring is optionally independently substituted with one     or more substituents independently selected from hydroxy, halo, oxo,     C₁-C₆ alkyl, C₁-C₆ alkoxy, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

-   In some embodiments, m=1; n=1; and

-   R¹ and R² are on adjacent atoms, and taken together with the atoms     connecting them, form a C₄-C₈ carbocyclic ring or a 5- to 8-membered     heterocyclic ring containing 1 or 2 heteroatoms independently     selected from O, N, and S, wherein the carbocyclic ring or     heterocyclic ring is unsubstituted.

In some embodiments, it is provided that:

(1) one or more of R¹ or R², when present, is selected from NR^(8′)R^(9′), C(O)NR^(8′)R^(9′), S(O)₂NR^(11′)R^(12′), C(O)R^(13′), C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, and 5- to 10-membered heteroaryl,

wherein each of the C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl is substituted with NR^(8′)R^(9′), C(O)NR^(8′)R^(9′), R^(15′), C₁-C₆ haloalkoxy, or C₃-C₇ cycloalkyl;

wherein each of the C₁-C₆ alkyl and C₁-C₆ haloalkyl is substituted with NR^(8′)R^(9′), C(O)NR^(8′)R^(9′), R¹⁵, C₁-C₆ haloalkoxy, or C₃-C₇ cycloalkyl;

and

each of the C₁-C₆ alkoxy, C₆-C₁₀ aryl and 5- to 10-membered heteroaryl is substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);

or

(2) one pair of R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one ring that is selected from:

(a) C₄-C₈ carbocyclic ring or 5- to-8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is independently substituted with one or more substituents each independently selected from from C₂-C₆ alkenyl, C₂-C₆ alkynyl, OC₃-C₁₀ cycloalkyl, CN, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl, wherein the S(O₂)C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

(b) C₄-C₈ carbocyclic ring or 5- to-8-membered heterocyclic ring containing 3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; and

(c) monocyclic or bicyclic C₉-C₁₂ carbocyclic ring or monocyclic or bicyclic 9- to 12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹;

each of R^(8′) and R^(9′) at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR¹¹R¹²;

or R^(8′) and R^(9′) taken together with the nitrogen they are attached to form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆ alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

provided that:

(1) one or more occurrences of R^(8′) or R^(9′) is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₇ cycloalkyl, (C═NR^(13′))NR^(11′)R^(12′), S(O₂)NR^(11′)R^(12′), C(O)R^(13′), CO₂R^(13′) and CONR^(11′)R^(12′); wherein the C₁-C₆ alkyl is substituted with NR¹¹R¹²; or

(2) one or more pairs of R^(8′) and R^(9′) attached to the same nitrogen taken together with the nitrogen they are attached to form:

(a) a 8- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆ alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy; or

(b) a 3- to 7-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆ alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

each of R^(11′) and R^(12′) at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, and —(Z¹—Z²)_(a1)—Z³, provided that one or more occurrences of R^(11′) and R^(12′) is —(Z¹—Z²)_(a1)—Z³;

R^(13′) is —(Z¹—Z²)_(a1)—Z^(3′), wherein

when a1 is 0, Z^(3′) is independently C₆₋₁₀ aryl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, each of which is substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy;

when a1 is 1-10 (e.g., 1-4), Z^(3′) is an independently selected Z³;

R¹⁵′ is —(Z⁴—Z⁵)_(a2′)—Z⁶;

a2′ is an integer selected from 2-10 (e.g., 2-5);

each Z⁴ is independently selected from —O—, —S—, —NH—, and —N(C₁-C₃ alkyl)-;

provided that the Z⁴ group directly attached to R¹ or R² is —O— or —S—;

each Z⁵ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z⁶ is OH, OC₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, NHC(O)(C₁-C₆ alkyl), NHC(O)(C₁-C₆ alkoxy), or an optionally substituted group selected from the group consisting of:

C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxyl.

In some embodiments, R¹′ is selected from the group consisting of:

methyl substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);

C₂-C₆ alkyl; C₁-C₆ haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂; CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀ aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl; NR⁸R⁹; C(O)R¹³; CONR⁸R⁹; SF₅; SC₁-C₆ alkyl; S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl; S(O₂)NR¹¹R¹²; C₃-C₇ cycloalkyl; and 3- to 7-membered heterocycloalkyl,

wherein the C₂-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl); and

wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R^(1′) C₃-C₇ cycloalkyl or of the R^(1′) 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, —O(C₀-C₃ alkylene)C₆-C₁₀ aryl, NR⁸R⁹, or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl.

In some embodiments, one pair of R¹ and R² is on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring (e.g., C₅ or C₆ carbocyclic ring) or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 (e.g., 1-2, e.g., 2) heteroatoms independently selected from O, N, and S (e.g., tetrahydropyridine, dihydrofuran, or dihydropyran), wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl (e.g., methyl), C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy (e.g., methoxy, ethoxy, isopropoxyl), OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or oxetanyl), and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo (e.g., fluoro), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹ (e.g., amino, methylamino, or dimethylamino), ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, one pair of R¹ and R² is on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₅-C₆ carbocyclic ring,

wherein the carbocyclic is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino; or

one pair of R¹ and R² on adjacent atoms taken together forms a moiety selected from:

each of which is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino.

In some embodiments, one pair of R¹ and R² is on adjacent atoms, and taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic C₄-C₁₂ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino.

In some embodiments, one pair of R¹ and R² is on adjacent atoms, and taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino.

In some embodiments, each of R¹ and R², when present, is independently selected from the group consisting of C₁-C₆ alkyl optionally substituted with one or more hydroxy, halo, oxo, C₁-C₆ alkoxy, 3- to 7-membered heterocycloalkyl optionally substituted with halo, C₃-C₇ cycloalkyl, R¹⁵, C₁-C₆ haloalkoxy, C₆-C₁₀ aryl optionally substituted with OC₁-C₆ alkyl, or NR⁸R⁹; C₃-C₇ cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C₁-C₆ alkoxy, C₁-C₆ alkyl, or NR⁸R⁹ wherein the C₁-C₆ salkoxy or C₁-C₆ alkyl is further optionally substituted with one to three hydroxy, halo, NR⁸R⁹, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C₁-C₆ alkyl, or NR⁸R⁹ wherein the C₁-C₆ alkoxy or C₁-C₆ alkyl is further optionally substituted with one to three hydroxy, halo, NR⁸R⁹, or oxo; C₁-C₆ haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; CO—C₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀ aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; S(O₂)NR¹¹R¹²; S(O)C₁-C₆ alkyl; and S(O₂)C₁-C₆ alkyl.

In certain embodiments, R¹ is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; isobutyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; 1,2,3-trihydroxy-2-propyl; 1-amino-2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; 1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl; 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl; 1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; 1-(2-methoxyethoxy)-2-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; pyrrolidinyl; 1,3-dioxolan-2-yl; COCH₃; COCH₂CH₃; difluoromethoxy; 2-methoxy-2-propyl; (methylamino)methyl; (2,2-difluoroeth-1-yl)(methyl)aminomethyl; (2,2,2-trifluoroeth-1-yl)(methyl)aminomethyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; 2-((methyl)aminomethyl)-prop-2-yl; 2-((methyl)amino)-prop-2-yl; (methyl)(cyclopropylmethyl)aminomethyl; (methyl)(2-(dimethylamino)eth-1-yl)aminomethyl; (cyclobutyl)(methyl)aminomethyl; 1-(cyclobutyl)amino-eth-1-yl; isopropylaminomethyl; (cyclobutyl)aminomethyl; cycloheptylaminomethyl; tetrahydropyranylaminomethyl; sec-butylaminomethyl; ethylaminomethyl; allylaminomethyl; (2,2-difluoroeth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)(methyl)aminomethyl; 2-fluoro-1-dimethylamino-eth-1-yl; 1-dimethylamino-2,2-difluoroeth-1-yl; 1-dimethylamino-2,2,2-trifluoroeth-1-yl; 1-dimethylamino-2,2,2-trimethyleth-1-yl; dimethylamino(cyclopropyl)methyl; methoxymethyl; isopropyl(methyl)amino; fluoro; chloro; phenyl; pyridyl; pyrazolyl; azetidinyl; 5-methyl-oxazolidin-2-one-5-yl; S(O₂)CH₃; S(O₂)NR¹¹R¹²; (3,3-difluoropyrrolidin-1-yl)methyl; 1-(difluoromethoxyl)eth-1-yl; azetidinylmethyl; 1-((methyl)aminomethyl)-cycloprop-1-yl; 4-methoxybenzyl; 4-methyl-piperazin-1-yl; morpholinylmethyl; and cyclopentyl.

In certain of any of the foregoing embodiments, R² is selected from the group consisting of fluoro, chloro, cyano, methyl; methoxy; ethoxy; isopropyl; 1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; COCH₃; COPh; 2-methoxy-2-propyl; methoxymethyl; (dimethylamino)methyl; S(O₂)CH₃; and S(O₂)NR¹¹R¹².

In some embodiments, one or more R¹ when present is independently a C₁-C₆ alkyl substituted with one or more hydroxy.

In certain of these embodiments, one or more R¹ is independently selected from 1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; and 1,2,3-trihydroxy-2-propyl.

In some embodiments, one or more R¹ when present is independently a C₁-C₆ alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) NR⁸R⁹.

In certain of these embodiments, one or more R¹ is independently selected from 1-amino-2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; and 1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl.

In some embodiments, one or more R¹ when present is independently a C₁-C₆ alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) R¹⁵.

In certain of these embodiments (e.g., a2=1 or 2), one or more R¹ is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl; 1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.

In certain of these embodiments (e.g., a2=1), one or more R¹ is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.

In certain embodiments (e.g., a2=1), one or more R¹ is independently selected from:

In certain embodiments (e.g., a2>1), one or more R¹ is

In some embodiments, one or more R¹ is independently C₁-C₆ alkyl substituted with one or more (e.g., one) NR⁸R⁹ and further optionally substituted with one or more halo.

In certain of these embodiments, one or more R¹ is independently selected from: (methylamino)methyl; (2,2-difluoroeth-1-yl)(methyl)aminomethyl; (2,2,2-trifluoroeth-1-yl)(methyl)aminomethyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; 2-((methyl)aminomethyl)-prop-2-yl; 2-((methyl)amino)-prop-2-yl; (methyl)(cyclopropylmethyl)aminomethyl; (methyl)(2-(dimethylamino)eth-1-yl)aminomethyl; (cyclobutyl)(methyl)aminomethyl; 1-(cyclobutyl)amino-eth-1-yl; isopropylaminomethyl; (cyclobutyl)aminomethyl; cycloheptylaminomethyl; tetrahydropyranylaminomethyl; sec-butylaminomethyl; ethylaminomethyl; allylaminomethyl; (2,2-difluoroeth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)(methyl)aminomethyl; 2-fluoro-1-dimethylamino-eth-1-yl; 1-dimethylamino-2,2-difluoroeth-1-yl; 1-dimethylamino-2,2,2-trifluoroeth-1-yl; 1-dimethylamino-2,2,2-trimethyleth-1-yl; and dimethylamino(cyclopropyl)methyl (e.g., one or more R¹ is dimethylaminomethyl or methylaminomethyl).

In some embodiments, one or more R¹ is C₁-C₆ alkyl that is optionally substituted with one or more halo. In certain of these embodiments, one or more R¹ is C₂-C₆ alkyl that is optionally substituted with one or more halo. As non-limiting examples, R¹ is ethyl or difluoromethyl.

In certain of any of the foregoing embodiments of R¹, one or more R² is independently selected from C₁-C₆ alkyl, C₁-C₆ alkyl optionally substituted with one or more hydroxy, C₁-C₆ alkyl optionally substituted with one or more C₁-C₆ alkoxy, and halo.

Particular Embodiments wherein m=1 and n=0 or when (AA-3) Applies

-   In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with     one or more hydroxy. -   In certain of these embodiments, R¹ is independently selected from     1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl;     1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl;     1,2-dihydroxy-2-propyl; and 1,2,3-trihydroxy-2-propyl. -   In some embodiments, R¹ is 1-hydroxy-2-methylpropan-2-yl. -   In some embodiments, R¹ is 2-hydroxy-2-propyl. -   In some embodiments, R¹ is hydroxymethyl. -   In some embodiments, R¹ is 1-hydroxyethyl. -   In some embodiments, R¹ is 1-hydroxy-2-propyl. -   In some embodiments, R¹ is 2-hydroxyethyl. -   In some embodiments, R¹ is 1,2-dihydroxy-2-propyl. -   In some embodiments, R¹ is 1,2,3-trihydroxy-2-propyl. -   In some embodiments, R¹ is C₁-C₆ alkyl. -   In some embodiments, R¹ is isobutyl. -   In some embodiments, R¹ is methyl. -   In some embodiments, R¹ is isopropyl. -   In some embodiments, R¹ is isopropyl. -   In some embodiments, R¹ is C₁-C₆ alkyl substituted with hydroxy at     the carbon directly connected to ring A. -   In some embodiments, R¹ is 2-hydroxy-2-propyl. -   In some embodiments, R¹ is hydroxymethyl. -   In some embodiments, R¹ is 1-hydroxyethyl. -   In some embodiments, R¹ is 1-hydroxy-2-propyl. -   In some embodiments, R¹ is C₁-C₆ alkyl substituted with two or more     hydroxy groups. -   In some embodiments, R¹ is C₁-C₆ alkyl substituted with two or more     hydroxy groups, wherein one of the two or more hydroxy groups is     bonded to the carbon directly connected to ring A. -   In some embodiments, R¹ is 1,2-dihydroxy-prop-2-yl. -   In some embodiments, R¹ is a C₁-C₆ alkyl substituted with one or     more hydroxy and further substituted with one or more (e.g., one)     NR⁸R⁹. -   In certain of these embodiments, R¹ is independently selected from     1-amino-2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; and     1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl. -   In some embodiments, R¹ is 1-amino-2-hydroxy-prop-2-yl. -   In some embodiments, R¹ is 1-acetamido-2-hydroxy-prop-2-yl. -   In some embodiments, R¹ is     1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl. -   In some embodiments, R¹ is independently a C₁-C₆ alkyl substituted     with one or more hydroxy and further substituted with one or more     (e.g., one) R¹⁵. -   In certain of these embodiments, a2 is 1 in R¹⁵. -   In certain of the foregoing embodiments, one or more R¹ is     independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl;     1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; and     1-(2-methoxyethoxy)-2-hydroxy-2-propyl. -   In certain embodiments, R¹ is

-   In certain embodiments when R¹ is independently a C₁-C₆ alkyl     substituted with one or more hydroxy and further substituted with     one or more (e.g., one) R¹⁵, a2 is >1. -   In certain of these embodiments, R¹ is:

-   In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with     one or more R¹⁵. -   In some embodiments, R¹ is C₃-C₇ cycloalkyl optionally substituted     with one or more hydroxy. -   In some embodiments, R¹ is C₃-C₇ cycloalkyl (e.g., cyclopropyl or     cyclopentyl). -   In some embodiments, R¹ is C₃-C₇ cycloalkyl optionally substituted     with one or more C₁-C₆ alkyl wherein said C₁-C₆ alkyl is further     optionally substituted as described elsewhere herein. -   In some embodiments, R¹ is 1-((methyl)aminomethyl)-cycloprop-1-yl. -   In some embodiments, R¹ is C₃-C₇ cycloalkyl substituted with hydroxy     at the carbon directly connected to ring A. -   In some embodiments, R¹ is 1-hydroxy-1-cyclopropyl. -   In some embodiments, R¹ is 1-hydroxy-1-cyclobutyl. -   In some embodiments, R¹ is 1-hydroxy-1-cyclopentyl. -   In some embodiments, R¹ is 1-hydroxy-1-cyclohexyl. -   In some embodiments, R¹ is 3- to 7-membered heterocycloalkyl     optionally substituted with one or more hydroxy. -   In some embodiments, R¹ is 3- to 7-membered heterocycloalkyl. -   In some embodiments, R¹ is morpholinyl (e.g., 1-morpholinyl). -   In some embodiments, R¹ is azetidinyl. -   In some embodiments, R¹ is 1,3-dioxolan-2-yl. -   In some embodiments, R¹ is 3- to 7-membered heterocycloalkyl     optionally substituted with one or more C₁-C₆ alkyl. -   In some embodiments, R¹ is 1-methylpyrrolidin-2-yl. -   In some embodiments, R¹ is 3- to 7-membered heterocycloalkyl     substituted with hydroxy at the carbon directly connected to ring A. -   In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with     one or more oxo. -   In some embodiments, R¹ is COCH₃. -   In some embodiments, R¹ is COCH₂CH₃. -   In some embodiments, R¹ is C₃-C₇ cycloalkyl optionally substituted     with one or more oxo. -   In some embodiments, R¹ is 3- to 7-membered heterocycloalkyl     optionally substituted with one or more oxo. -   In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with     one or more C₁-C₆ alkoxy. -   In some embodiments, R¹ is 2-methoxy-2-propyl. -   In some embodiments, R¹ is methoxymethyl. -   In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with     one or more C₁-C₆ haloalkoxy. -   In some embodiments, R¹ is 1-(difluoromethoxyl)eth-1-yl. -   In some embodiments, R¹ is C₃-C₇ cycloalkyl optionally substituted     with one or more C₁-C₆ alkoxy. -   In some embodiments, R¹ is 3- to 7-membered heterocycloalkyl     optionally substituted with one or more C₁-C₆ alkoxy. -   In some embodiments, R¹ is 3- to 7-membered heterocycloalkyl     optionally substituted with one or more oxo and further optionally     substituted with one or more C₁-C₆ alkyl. -   In some embodiments, R¹ is 5-methyl-oxazolidin-2-one-5-yl. -   In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with     one or more NR⁸R⁹. -   In some embodiments, R¹ is C₁-C₆ alkyl substituted with NR⁸R⁹ at the     carbon directly connected to ring A. -   In some embodiments, R¹ is (methylamino)methyl. -   In some embodiments, R¹ is (dimethylamino)methyl. -   In some embodiments, R¹ is aminomethyl. -   In some embodiments, R¹ is N-methylacetamidomethyl. -   In some embodiments, R¹ is 1-(dimethylamino)eth-1-yl. -   In some embodiments, R¹ is 2-(dimethylamino)prop-2-yl. -   In some embodiments, R¹ is (2-methoxy-eth-1-yl)(methyl)aminomethyl. -   In some embodiments, R¹ is (methyl)(acetyl)aminomethyl. -   In some embodiments, R¹ is (methyl)(cyclopropylmethyl)aminomethyl. -   In some embodiments, R¹ is     (methyl)(2,2-difluoroeth-1-yl)aminomethyl. -   In some embodiments, R¹ is     (2,2,2-trifluoroeth-1-yl)(methyl)aminomethyl. -   In some embodiments, R¹ is 2-((methyl)aminomethyl)-prop-2-yl. -   In some embodiments, R¹ is 2-((methyl)amino)-prop-2-yl. -   In some embodiments, R¹ is (methyl)(cyclopropylmethyl)aminomethyl. -   In some embodiments, R¹ is     (methyl)(2-(dimethylamino)eth-1-yl)aminomethyl. -   In some embodiments, R¹ is (cyclobutyl)(methyl)aminomethyl. -   In some embodiments, R¹ is (2-methoxy-eth-1-yl)(methyl)aminomethyl. -   In some embodiments, R¹ is 2-fluoro-1-dimethylamino-eth-1-yl. -   In some embodiments, R¹ is 1-dimethylamino-2,2-difluoroeth-1-yl. -   In some embodiments, R¹ is 1-dimethylamino-2,2,2-trifluoroeth-1-yl. -   In some embodiments, R¹ is 1-dimethylamino-2,2,2-trimethyleth-1-yl. -   In some embodiments, R¹ is (cyclobutyl)(methyl)aminomethyl. -   In some embodiments, R¹ is isopropylaminomethyl. -   In some embodiments, R¹ is (cyclobutyl)aminomethyl. -   In some embodiments, R¹ is cycloheptylaminomethyl. -   In some embodiments, R¹ is tetrahydropyranylaminomethyl. -   In some embodiments, R¹ is sec-butylaminomethyl. -   In some embodiments, R¹ is ethylaminomethyl. -   In some embodiments, R¹ is allylaminomethyl. -   In some embodiments, R¹ is 2,2-difluoroeth-1-yl)aminomethyl. -   In some embodiments, R¹ is (2-methoxy-eth-1-yl)aminomethyl. -   In some embodiments, R¹ is C₁-C₆ alkyl substituted with NR⁸R⁹,     wherein said C₁-C₆ alkyl is further optionally substituted as     described elsewhere herein. -   In some embodiments, R¹ is dimethylamino(cyclopropyl)methyl. -   In some embodiments, R¹ is C₃-C₇ cycloalkyl optionally substituted     with one or more NR⁸R⁹. -   In some embodiments, R¹ is 3- to 7-membered heterocycloalkyl     optionally substituted with one or more NR⁸R⁹. -   In some embodiments, R¹ is C₁-C₆ haloalkyl optionally substituted     with one or more hydroxy. -   In some embodiments, R¹ is C₁-C₆ alkoxy that is optionally     substituted as defined elsewhere herein. -   In some embodiments, R¹ is C₁-C₆ alkoxy. -   In some embodiments, R¹ is C₁-C₆ haloalkoxy. -   In some embodiments, R¹ is difluoromethoxy. -   In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with     3- to 7-membered heterocycloalkyl, wherein the 3- to 7-membered     heterocycloalkyl is further optionally substituted as defined     elsewhere herein. -   In some embodiments, R¹ is pyrrolidinylmethyl (e.g.,     pyrrolidin-1-ylmethyl). -   In some embodiments, R¹ is optionally substituted pyrrolidinylmethyl     (e.g., 3,3-difluoropyrrolidin-1-ylmethyl). -   In some embodiments, R¹ is azetidinylmethyl (e.g.,     azetidin-1-ylmethyl). -   In some embodiments, R¹ is optionally substituted azetidinylmethyl     (e.g., 3-methoxyazetidin-1-ylmethyl). -   In some embodiments, R¹ is morpholinylmethyl (e.g.,     morpholin-4-ylmethyl). -   In some embodiments, R¹ is 4-methyl-piperazin-1-yl. -   In some embodiments, R¹ is 3- to 7-membered heterocycloalkyl     optionally substituted with one or more hydroxy. In certain of these     embodiments, R¹ is further optionally substituted with one or more     C₁-C₆ alkyl, wherein each of said C₁-C₆ alkyl is further optionally     substituted as defined anywhere herein. As a non-limiting example,     R¹ is

-   In some embodiments, R¹ is 3- to 7-membered heterocycloalkyl     optionally substituted with one or more substituents independently     selected from hydroxy and R¹⁵. In certain of these embodiments, R¹     is further optionally substituted with one or more C₁-C₆ alkyl,     wherein each of said C₁-C₆ alkyl is further optionally substituted     as defined anywhere herein. As a non-limiting example, R¹ is

-   In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with     one or more C₆-C₁₀ aryl, wherein said aryl is further optionally     substituted as described elsewhere herein. -   In some embodiments, R¹ is 4-methoxybenzyl. -   In some embodiments, R¹ is halo. -   In some embodiments, R¹ is fluoro. -   In some embodiments, R¹ is chloro. -   In some embodiments, R¹ is CN. -   In some embodiments, R¹ is NO₂. -   In some embodiments, R¹ is COC₁-C₆ alkyl. -   In some embodiments, R¹ is CO—C₆-C₁₀ aryl. -   In some embodiments, R¹ is CO(5- to 10-membered heteroaryl). -   In some embodiments, R¹ is CO₂C₁-C₆ alkyl. -   In some embodiments, R¹ is CO₂C₃-C₈ cycloalkyl. -   In some embodiments, R¹ is OCOC₁-C₆ alkyl. -   In some embodiments, R¹ is OCOC₆-C₁₀ aryl. -   In some embodiments, R¹ is OCO(5- to 10-membered heteroaryl). -   In some embodiments, R¹ is OCO(3- to 7-membered heterocycloalkyl). -   In some embodiments, R¹ is C₆-C₁₀ aryl. -   In some embodiments, R¹ is phenyl. -   In some embodiments, R¹ is 5- to 10-membered heteroaryl. -   In some embodiments, R¹ is pyridyl (e.g., 4-pyridyl). -   In some embodiments, R¹ is pyrazolyl (e.g., 1-pyrazolyl). -   In some embodiments, R¹ is NH₂. -   In some embodiments, R¹ is NHC₁-C₆ alkyl. -   In some embodiments, R¹ is N(C₁-C₆ alkyl)₂. -   In some embodiments, R¹ is CONR⁸R⁹. -   In some embodiments, R¹ is SF₅. -   In some embodiments, R¹ is SC₁-C₆ alkyl, -   In some embodiments, R¹ is S(O₂)C₁-C₆ alkyl. -   In some embodiments, R¹ is S(O₂)CH₃. -   In some embodiments, R¹ is S(O₂)NR¹¹R¹². -   In some embodiments, R¹ is S(O₂)N(CH₃)₂. -   In some embodiments, R¹ is S(O)C₁-C₆ alkyl. -   In some embodiments, R¹ is S(O)CH₃. -   In some embodiments, R¹ is attached to a carbon of an aryl ring A. -   In some embodiments, R¹ is attached to a carbon of a heteroaryl ring     A. -   In some embodiments, R¹ is attached to a nitrogen of a heteroaryl     ring A.

Particular Embodiments wherein m=1 and n=1

-   In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with     one or more hydroxy, and R² is C₁-C₆ alkyl optionally substituted     with one or more hydroxy. -   In some embodiments, R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is     methyl. -   In some embodiments, R¹ is 2-hydroxy-2-propyl and R² is methyl. -   In some embodiments, R¹ is 2-hydroxy-2-propyl and R² is isopropyl. -   In some embodiments, R¹ is 2-hydroxy-2-propyl and R² is     2-hydroxy-2-propyl. -   In some embodiments, R¹ is 2-hydroxy-2-propyl and R² is     1-hydroxyethyl. -   In some embodiments, R¹ is hydroxymethyl and R² is methyl. -   In some embodiments, R¹ is 1-hydroxyethyl and R² is methyl. -   In some embodiments, R¹ is 2-hydroxyethyl and R² is methyl. -   In some embodiments, R¹ is 1-hydroxy-2-propyl and R² is methyl. -   In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with     one or more hydroxy, and R² is C₆-C₁₀ aryl. -   In some embodiments, R¹ is 2-hydroxy-2-propyl and R² is phenyl. -   In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with     one or more hydroxy, and R² is 5- to 10-membered heteroaryl. -   In some embodiments, R¹ is 2-hydroxy-2-propyl and R² is pyridyl. -   In some embodiments, R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl. -   In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with     one or more hydroxy, and R² is SF₅. -   In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with     one or more hydroxy, and R² is SC₁-C₆ alkyl, -   In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with     one or more hydroxy, and R² is S(O₂)C₁-C₆ alkyl. -   In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with     one or more hydroxy, and R² is S(O₂)CH₃. -   In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with     one or more hydroxy, and R² is halo. -   In some embodiments, R¹ is 2-hydroxy-2-propyl and R² is chloro. -   In some embodiments, R¹ is 2-hydroxy-2-propyl and R² is fluoro. -   In some embodiments, R¹ is 1,2-dihydroxy-2-propyl and R² is fluoro. -   In some embodiments, R¹ is 1,2-dihydroxy-2-propyl and R² is chloro. -   In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with     one or more hydroxy, and R² is C₁-C₆ alkyl optionally substituted     with one or more C₁-C₆ alkoxy. -   In some embodiments, R¹ is 2-hydroxy-2-propyl and R² is     methoxymethyl. -   In some embodiments, R¹ is C₃-C₇ cycloalkyl optionally substituted     with one or more hydroxy, and R² is C₁-C₆ alkyl. -   In some embodiments, R¹ is 1-hydroxy-1-cyclopropyl, and R² is     methyl. -   In some embodiments, R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl. -   In some embodiments, R¹ is 1-hydroxy-1-cyclopentyl, and R² is     methyl. -   In some embodiments, R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl. -   In some embodiments, R¹ is 3- to 7-membered heterocycloalkyl     optionally substituted with one or more hydroxy, and R² is C₁-C₆     alkyl. -   In some embodiments, R¹ is morpholinyl, and R² is methyl. -   In some embodiments, R¹ is 1,3-dioxolan-2-yl, and R² is methyl. -   In some embodiments, R¹ is 3- to 7-membered heterocycloalkyl     optionally substituted with one or more hydroxy, and R² is halo. -   In some embodiments, R¹ is 1,3-dioxolan-2-yl, and R² is fluoro. -   In some embodiments, R¹ is 1,3-dioxolan-2-yl, and R² is chloro. -   In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with     one or more oxo, and R² is methyl. -   In some embodiments, R¹ is COCH₃, and R² is methyl. -   In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with     one or more C₁-C₆ alkoxy, and R² is C₁-C₆ alkyl. -   In some embodiments, R¹ is 2-methoxy-2-propyl, and R² is methyl. -   In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with     one or more NR⁸R⁹, and R² is C₁-C₆ alkyl. -   In some embodiments, R¹ is (dimethylamino)methyl, and R² is methyl. -   In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with     one or more NR⁸R⁹, and R² is halo. -   In some embodiments, R¹ is (dimethylamino)methyl, and R² is fluoro. -   In some embodiments, R¹ is (dimethylamino)methyl, and R² is fluoro. -   In some embodiments, R¹ is (methylamino)methyl, and R² is fluoro. -   In some embodiments, R¹ is aminomethyl, and R² is fluoro. -   In some embodiments, R¹ is C₁-C₆ alkyl, and R² is C₁-C₆ alkyl. -   In some embodiments, R¹ is methyl, and R² is methyl. -   In some embodiments, R¹ is C₁-C₆ alkyl substituted with one or more     hydroxy; and R² is C₁-C₆ alkyl substituted with one or more hydroxy.     In certain of the foregoing embodiments, R¹ or R² is further     optionally substituted as defined elsewhere herein (e.g., R¹ or R²     is further optionally substituted with one R¹⁵). -   In some embodiments, R¹ is C₁-C₆ alkyl substituted with one or more     hydroxy; and R² is hydroxymethyl. -   In some embodiments, R¹ is 1,3-dihydroxy-2-methyl-2-propyl; and R²     is hydroxymethyl. -   In some embodiments, R¹ is 2-hydroxymethyl-2-propyl; and R² is     hydroxymethyl. -   In some embodiments, R¹ is 2-hydroxyeth-1-yl; and R² is     hydroxymethyl. -   In some embodiments, R¹ is 1,2-dihydroxy-3-propyl; and R² is     hydroxymethyl. -   In some embodiments, R¹ is 1,2,3-trihydroxy-2-propyl; and R² is     hydroxymethyl. -   In some embodiments, R¹ is 2-hydroxy-2-propyl; and R² is     hydroxymethyl. -   In some embodiments, R¹ is 1,2-dihydroxy-2-propyl; and R² is     hydroxymethyl. -   In some embodiments, R¹ is:

and R² is hydroxymethyl.

-   In some embodiments, R² is C₁-C₆ alkyl substituted with one or more     hydroxy; and R¹ is hydroxymethyl. -   In some embodiments, R² is 1,3-dihydroxy-2-methyl-2-propyl; and R¹     is hydroxymethyl. -   In some embodiments, R² is 2-hydroxymethyl-2-propyl; and R¹ is     hydroxymethyl. -   In some embodiments, R² is 2-hydroxyeth-1-yl; and R¹ is     hydroxymethyl. -   In some embodiments, R² is 1,2-dihydroxy-3-propyl; and R¹ is     hydroxymethyl. -   In some embodiments, R² is 1,2,3-trihydroxy-2-propyl; and R¹ is     hydroxymethyl. -   In some embodiments, R² is 2-hydroxy-2-propyl; and R¹ is     hydroxymethyl. -   In some embodiments, R² is 1,2-dihydroxy-2-propyl; and R¹ is     hydroxymethyl. -   In some embodiments, R² is:

and R¹ is hydroxymethyl.

-   In some embodiments, R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is     methyl. -   In some embodiments, R² is 2-hydroxy-2-propyl and R¹ is methyl. -   In some embodiments, R² is 2-hydroxy-2-propyl and R¹ is isopropyl. -   In some embodiments, R² is 2-hydroxy-2-propyl and R¹ is     1-hydroxyethyl. -   In some embodiments, R² is hydroxymethyl and R¹ is methyl. -   In some embodiments, R² is 1-hydroxyethyl and R¹ is methyl. -   In some embodiments, R² is 2-hydroxyethyl and R¹ is methyl. -   In some embodiments, R² is 1-hydroxy-2-propyl and R¹ is methyl. -   In some embodiments, R² is C₁-C₆ alkyl optionally substituted with     one or more hydroxy, and R¹ is C₆-C₁₀ aryl. -   In some embodiments, R² is 2-hydroxy-2-propyl and R¹ is phenyl. -   In some embodiments, R² is C₁-C₆ alkyl optionally substituted with     one or more hydroxy, and R¹ is 5- to 10-membered heteroaryl. -   In some embodiments, R² is 2-hydroxy-2-propyl and R¹ is pyridyl. -   In some embodiments, R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl. -   In some embodiments, R² is C₁-C₆ alkyl optionally substituted with     one or more hydroxy, and R¹ is SF₅. -   In some embodiments, R² is C₁-C₆ alkyl optionally substituted with     one or more hydroxy, and R¹ is SC₁-C₆ alkyl. -   In some embodiments, R² is C₁-C₆ alkyl optionally substituted with     one or more hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl. -   In some embodiments, R² is C₁-C₆ alkyl optionally substituted with     one or more hydroxy, and R¹ is S(O₂)CH₃. -   In some embodiments, R² is C₁-C₆ alkyl optionally substituted with     one or more hydroxy, and R¹ is halo. -   In some embodiments, R² is 2-hydroxy-2-propyl and R¹ is chloro. -   In some embodiments, R² is 2-hydroxy-2-propyl and R¹ is fluoro. -   In some embodiments, R² is 1,2-dihydroxy-2-propyl and R¹ is fluoro. -   In some embodiments, R² is 1,2-dihydroxy-2-propyl and R¹ is chloro. -   In some embodiments, R¹ is C₁-C₆ alkyl optionally substituted with     one or more hydroxy, and R² is C₁-C₆ alkyl optionally substituted     with one or more C₁-C₆ alkoxy. -   In some embodiments, R¹ is 2-hydroxy-2-propyl and R² is     methoxymethyl. -   In some embodiments, R² is C₃-C₇ cycloalkyl optionally substituted     with one or more hydroxy, and R¹ is C₁-C₆ alkyl. -   In some embodiments, R² is 1-hydroxy-1-cyclopropyl, and R¹ is     methyl. -   In some embodiments, R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl. -   In some embodiments, R² is 1-hydroxy-1-cyclopentyl, and R¹ is     methyl. -   In some embodiments, R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl. -   In some embodiments, R² is 3- to 7-membered heterocycloalkyl     optionally substituted with one or more hydroxy, and R¹ is C₁-C₆     alkyl. -   In some embodiments, R² is morpholinyl, and R¹ is methyl. -   In some embodiments, R² is 1,3-dioxolan-2-yl, and R¹ is methyl. -   In some embodiments, R² is 3- to 7-membered heterocycloalkyl     optionally substituted with one or more hydroxy, and R¹ is halo. -   In some embodiments, R² is 1,3-dioxolan-2-yl, and R¹ is fluoro. -   In some embodiments, R² is 1,3-dioxolan-2-yl, and R¹ is chloro. -   In some embodiments, R² is C₁-C₆ alkyl optionally substituted with     one or more oxo, and R¹ is methyl. -   In some embodiments, R² is COCH₃, and R¹ is methyl. -   In some embodiments, R² is C₁-C₆ alkyl optionally substituted with     one or more C₁-C₆ alkoxy, and R¹ is C₁-C₆ alkyl. -   In some embodiments, R² is 2-methoxy-2-propyl, and R¹ is methyl. -   In some embodiments, R² is C₁-C₆ alkyl optionally substituted with     one or more NR⁸R⁹, and R¹ is C₁-C₆ alkyl. -   In some embodiments, R² is (dimethylamino)methyl, and R¹ is methyl. -   In some embodiments, R² is C₁-C₆ alkyl optionally substituted with     one or more NR⁸R⁹, and R¹ is halo. -   In some embodiments, R² is (dimethylamino)methyl, and R¹ is fluoro. -   In some embodiments, R² is (methylamino)methyl, and R¹ is fluoro. -   In some embodiments, R² is aminomethyl, and R¹ is fluoro. -   In some embodiments, R² is C₁-C₆ alkoxy, and R¹ is C₁-C₆ alkyl     optionally substituted with one or more NR⁸R⁹. -   In some embodiments, R² is methoxy, and R¹ is (dimethylamino)methyl. -   In some embodiments, R¹ and R² are each attached to a carbon of an     aryl ring A. -   In some embodiments, R¹ and R² are each attached to a carbon of a     heteroaryl ring A. -   In some embodiments, R¹ is attached to a carbon and R² is attached     to a nitrogen of a heteroaryl ring A. -   In some embodiments, R² is attached to a carbon and R¹ is attached     to a nitrogen of a heteroaryl ring A. -   In some embodiments, R¹ and R² are on adjacent atoms, and taken     together with the atoms connecting them, form a C₅ carbocyclic ring     optionally substituted with one or more substituents independently     selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,     ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, R¹ and R² are on adjacent atoms, and taken     together with the atoms connecting them, form a C₅ aliphatic     carbocyclic ring. -   In some embodiments, R¹ and R² are on adjacent atoms, and taken     together with the atoms connecting them, form a C₆ carbocyclic ring     optionally substituted with one or more substituents independently     selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,     ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, R¹ and R² are on adjacent atoms, and taken     together with the atoms connecting them, form a C₆ aliphatic     carbocyclic ring. -   In some embodiments, R¹ and R² are on adjacent atoms, and taken     together with the atoms connecting them, form a C₆ aromatic     carbocyclic ring. -   In some embodiments, R¹ and R² are on adjacent atoms, and taken     together with the atoms connecting them, form a 5-membered     heterocyclic ring containing 1 or 2 heteroatoms independently     selected from O, N, and S, optionally substituted with one or more     substituents independently selected from hydroxy, halo, oxo, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and     CONR⁸R⁹. -   In some embodiments, R¹ and R² are on adjacent atoms, and taken     together with the atoms connecting them, form a 5-membered aliphatic     heterocyclic ring containing 1 or 2 heteroatoms independently     selected from O, N, and S. -   In some embodiments, R¹ and R² are on adjacent atoms, and taken     together with the atoms connecting them, form a 5-membered     heteroaromatic ring containing 1 or 2 heteroatoms independently     selected from O, N, and S. -   In some embodiments, R¹ and R² are on adjacent atoms, and taken     together with the atoms connecting them, form a 6-membered     heterocyclic ring containing 1 or 2 heteroatoms independently     selected from O, N, and S, optionally substituted with one or more     substituents independently selected from hydroxy, halo, oxo, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and     CONR⁸R⁹. -   In some embodiments, R¹ and R² are on adjacent atoms, and taken     together with the atoms connecting them, form a 6-membered aliphatic     heterocyclic ring containing 1 or 2 heteroatoms independently     selected from O, N, and S. -   In some embodiments, R¹ and R² are on adjacent atoms, and taken     together with the atoms connecting them, form a 6-membered     heteroaromatic ring containing 1 or 2 heteroatoms independently     selected from O, N, and S. -   In some embodiments, R¹ and R² are different. -   In some embodiments, R¹ and R² are different, and R² comprises a     carbonyl group. -   In some embodiments, R¹ and R² are different, and R² comprises 1 or     2 (e.g., 1) nitrogen atoms. -   In some embodiments, R¹ and R² are different, and R² comprises 1 or     2 (e.g., 1) oxygen atoms. -   In some embodiments, R¹ and R² are different, and R² comprises a     sulfur atom. -   In some embodiments, R² and R¹ are different, and R² comprises a     carbonyl group. -   In some embodiments, R² and R¹ are different, and R² comprises 1 or     2 (e.g., 1) nitrogen atoms. -   In some embodiments, R² and R¹ are different, and R² comprises 1 or     2 (e.g., 1) oxygen atoms. -   In some embodiments, R² and R¹ are different, and R² comprises a     sulfur atom. -   In some embodiments, R¹ and R² are the same. -   In some embodiments, R¹ is para or meta to R². -   In some embodiments, R¹ is para or ortho to R². -   In some embodiments, R¹ is ortho or meta to R². In some embodiments,     R¹ is para to R². -   In some embodiments, R¹ is meta to R². -   In some embodiments, R¹ is ortho to R².

Particular Embodiments of R^(1′) when (AA-4) Applies

-   In some embodiments, R^(1′) is C₂-C₆ alkyl optionally substituted     with one or more hydroxy. -   In some embodiments, R^(1′) is 1-hydroxy-2-methylpropan-2-yl. -   In some embodiments, R^(1′) is 2-hydroxyethyl. -   In some embodiments, R^(1′) is 1,2-dihydroxy-2-propyl. -   In some embodiments, R^(1′) is 1,2,3-trihydroxy-2-propyl. -   In some embodiments, R^(1′) is C₂-C₆ alkyl. -   In some embodiments, R^(1′) is isobutyl. -   In some embodiments, R^(1′) is isopropyl. -   In some embodiments, R^(1′) is C₂-C₆ alkyl substituted with hydroxy     at the carbon directly connected to ring A. -   In some embodiments, R^(1′) is 2-hydroxy-2-propyl. -   In some embodiments, R^(1′) is 1-hydroxyethyl. -   In some embodiments, R^(1′) is 1-hydroxy-2-propyl. -   In some embodiments, R^(1′) is hydroxymethyl. -   In some embodiments, R^(1′) is C₂-C₆ alkyl substituted with two or     more hydroxy groups. -   In some embodiments, R^(1′) is C₂-C₆ alkyl substituted with two or     more hydroxy groups, wherein one of the two or more hydroxy groups     is bonded to the carbon directly connected to ring A. -   In some embodiments, R¹′ is 1,2-dihydroxy-prop-2-yl. -   In some embodiments, R¹′ is a C₂-C₆ alkyl substituted with one or     more hydroxy and further substituted with one or more (e.g., one)     NR⁸R⁹. -   In certain of these embodiments, R¹′ is independently selected from     1-amino-2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; and     1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl. -   In some embodiments, R^(1′) is 1-amino-2-hydroxy-prop-2-yl. -   In some embodiments, R^(1′) is 1-acetamido-2-hydroxy-prop-2-yl. -   In some embodiments, R^(1′) is     1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl. -   In some embodiments, R^(1′) is independently a C₂-C₆ alkyl     substituted with one or more hydroxy and further substituted with     one or more (e.g., one) R¹⁵. -   In certain of these embodiments, a2 is 1 in R¹⁵. -   In certain of the foregoing embodiments, one or more R^(1′) is     independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl;     1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; and     1-(2-methoxyethoxy)-2-hydroxy-2-propyl. -   In certain embodiments, is

-   In certain embodiments when R^(1′) is independently a C₂-C₆ alkyl     substituted with one or more hydroxy and further substituted with     one or more (e.g., one) R¹⁵, a2 is >1. -   In certain of these embodiments, R¹′ is:

-   In some embodiments, R^(1′) is C₃-C₇ cycloalkyl optionally     substituted with one or more hydroxy. -   In some embodiments, R^(1′) is C₃-C₇ cycloalkyl (e.g., cyclopropyl     or cyclopentyl). -   In some embodiments, R^(1′) is C₃-C₇ cycloalkyl optionally     substituted with one or more C₁-C₆ alkyl wherein said C₁-C₆ alkyl is     further optionally substituted as described elsewhere herein. -   In some embodiments, R¹′ is 1-((methyl)aminomethyl)-cycloprop-1-yl. -   In some embodiments, R^(1′) is C₃-C₇ cycloalkyl substituted with     hydroxy at the carbon directly connected to ring A. -   In some embodiments, R^(1′) is 1-hydroxy-1-cyclopropyl. -   In some embodiments, R^(1′) is 1-hydroxy-1-cyclobutyl. -   In some embodiments, R^(1′) is 1-hydroxy-1-cyclopentyl. -   In some embodiments, R^(1′) is 1-hydroxy-1-cyclohexyl. -   In some embodiments, R^(1′) is 3- to 7-membered heterocycloalkyl     optionally substituted with one or more hydroxy. -   In some embodiments, R^(1′) is 3- to 7-membered heterocycloalkyl. -   In some embodiments, R^(1′) is morpholinyl (e.g., 1-morpholinyl). -   In some embodiments, R^(1′) is azetidinyl. -   In some embodiments, R^(1′) is 1,3-dioxolan-2-yl. -   In some embodiments, R^(1′) is 3- to 7-membered heterocycloalkyl     optionally substituted with one or more C₁-C₆ alkyl. -   In some embodiments, R^(1′) is 1-methylpyrrolidin-2-yl. -   In some embodiments, R^(1′) is 3- to 7-membered heterocycloalkyl     substituted with hydroxy at the carbon directly connected to ring A. -   In some embodiments, R^(1′) is C₂-C₆ alkyl optionally substituted     with one or more oxo. -   In some embodiments, R^(1′) is COCH₃. -   In some embodiments, R^(1′) is COCH₂CH₃. -   In some embodiments, R^(1′) is C₃-C₇ cycloalkyl optionally     substituted with one or more oxo. -   In some embodiments, R¹′ is 3- to 7-membered heterocycloalkyl     optionally substituted with one or more oxo. -   In some embodiments, R^(1′) is C₂-C₆ alkyl optionally substituted     with one or more C₁-C₆ alkoxy. -   In some embodiments, R^(1′) is 2-methoxy-2-propyl. -   In some embodiments, R^(1′) is methyl substituted with one or more     C₁-C₆ alkoxy. -   In some embodiments, R^(1′) is methoxymethyl. -   In some embodiments, R^(1′) is C₂-C₆ alkyl optionally substituted     with one or more C₁-C₆ haloalkoxy. -   In some embodiments, R^(1′) is 1-(difluoromethoxyl)eth-1-yl. -   In some embodiments, R^(1′) is C₃-C₇ cycloalkyl optionally     substituted with one or more C₁-C₆ alkoxy. -   In some embodiments, R^(1′) is 3- to 7-membered heterocycloalkyl     optionally substituted with one or more C₁-C₆ alkoxy. -   In some embodiments, R^(1′) is methyl substituted with one or more     (e.g., 1) NR⁸R⁹. -   In some embodiments, R^(1′) is (methylamino)methyl. -   In some embodiments, R^(1′) is (dimethylamino)methyl. -   In some embodiments, R^(1′) is aminomethyl. -   In some embodiments, R^(1′) is N-methylacetamidomethyl. -   In some embodiments, R^(1′) is     (2-methoxy-eth-1-yl)(methyl)aminomethyl. -   In some embodiments, R^(1′) is (methyl)(acetyl)aminomethyl. -   In some embodiments, R^(1′) is     (methyl)(cyclopropylmethyl)aminomethyl. -   In some embodiments, R^(1′) is     (methyl)(2,2-difluoroeth-1-yl)aminomethyl. -   In some embodiments, R^(1′) is     (2,2,2-trifluoroeth-1-yl)(methyl)aminomethyl. -   In some embodiments, R^(1′) is     (methyl)(2-(dimethylamino)eth-1-yl)aminomethyl. -   In some embodiments, R^(1′) is (cyclobutyl)(methyl)aminomethyl. -   In some embodiments, R^(1′) is     (2-methoxy-eth-1-yl)(methyl)aminomethyl. -   In some embodiments, R^(1′) is methyl substituted with NR⁸R⁹,     wherein said C₁-C₆ alkyl is further optionally substituted as     described elsewhere herein. -   In some embodiments, R^(1′) is dimethylamino(cyclopropyl)methyl. -   In some embodiments, R^(1′) is C₂-C₆ alkyl substituted with NR⁸R⁹,     wherein said C₂-C₆ alkyl is further optionally substituted as     described elsewhere herein. -   In some embodiments, R^(1′) is C₂-C₆ alkyl optionally substituted     with one or more NR⁸R⁹. -   In some embodiments, R^(1′) is C₂-C₆ alkyl substituted with NR⁸R⁹ at     the carbon directly connected to ring A. -   In some embodiments, R^(1′) is 1-(dimethylamino)eth-1-yl. -   In some embodiments, R^(1′) is 2-(dimethylamino)prop-2-yl. -   In some embodiments, R^(1′) is 2-((methyl)aminomethyl)-prop-2-yl. -   In some embodiments, R^(1′) is 2-((methyl)amino)-prop-2-yl. -   In some embodiments, R^(1′) is 2-fluoro-1-dimethylamino-eth-1-yl. -   In some embodiments, R^(1′) is 1-dimethylamino-2,2-difluoroeth-1-yl. -   In some embodiments, R^(1′) is     1-dimethylamino-2,2,2-trifluoroeth-1-yl. -   In some embodiments, R^(1′) is     1-dimethylamino-2,2,2-trimethyleth-1-yl. -   In some embodiments, R^(1′) is (cyclobutyl)(methyl)aminomethyl. -   In some embodiments, R^(1′) is isopropylaminomethyl. -   In some embodiments, R^(1′) is (cyclobutyl)aminomethyl. -   In some embodiments, R^(1′) is cycloheptylaminomethyl. -   In some embodiments, R^(1′) is tetrahydropyranylaminomethyl. -   In some embodiments, R^(1′) is sec-butylaminomethyl. -   In some embodiments, R^(1′) is ethylaminomethyl. -   In some embodiments, R^(1′) is allylaminomethyl. -   In some embodiments, R^(1′) is 2,2-difluoroeth-1-yl)aminomethyl. -   In some embodiments, R^(1′) is (2-methoxy-eth-1-yl)aminomethyl. -   In some embodiments, R^(1′) is C₃-C₇ cycloalkyl optionally     substituted with one or more NR⁸R⁹. -   In some embodiments, R^(1′) is 3- to 7-membered heterocycloalkyl     optionally substituted with one or more NR⁸R⁹. -   In some embodiments, R^(1′) is C₁-C₆ haloalkyl optionally     substituted with one or more hydroxy. -   In some embodiments, R^(1′) is C₁-C₆ alkoxy. -   In some embodiments, R^(1′) is C₁-C₆ haloalkoxy. -   In some embodiments, R^(1′) is difluoromethoxy. -   In some embodiments, R^(1′) is C₂-C₆ alkyl optionally substituted     with 3- to 7-membered heterocycloalkyl, wherein the 3- to 7-membered     heterocycloalkyl is further optionally substituted as defined     elsewhere herein. -   In some embodiments, R^(1′) is methyl substituted with 3- to     7-membered heterocycloalkyl, wherein the 3- to 7-membered     heterocycloalkyl is further optionally substituted as defined     elsewhere herein. -   In some embodiments, R^(1′) is pyrrolidinylmethyl (e.g.,     pyrrolidin-1-ylmethyl). -   In some embodiments, R^(1′) is optionally substituted     pyrrolidinylmethyl (e.g., 3,3-difluoropyrrolidin-1-ylmethyl). -   In some embodiments, R^(1′) is azetidinylmethyl (e.g.,     azetidin-1-ylmethyl). -   In some embodiments, R^(1′) is optionally substituted     azetidinylmethyl (e.g., 3-methoxyazetidin-1-ylmethyl). -   In some embodiments, R^(1′) is morpholinylmethyl (e.g.,     morpholin-4-ylmethyl). -   In some embodiments, R^(1′) is 4-methyl-piperazin-1-yl. -   In some embodiments, R^(1′) is C₂-C₆ alkyl optionally substituted     with one or more C₆-C₁₀ aryl, wherein said aryl is further     optionally substituted as described elsewhere herein. -   In some embodiments, R^(1′) is methyl substituted with C₆-C₁₀ aryl,     wherein said aryl is further optionally substituted as described     elsewhere herein. -   In some embodiments, R^(1′) is 4-methoxybenzyl. -   In some embodiments, R^(1′) is halo. -   In some embodiments, R^(1′) is fluoro. -   In some embodiments, R^(1′) is chloro. -   In some embodiments, R^(1′) is CN. -   In some embodiments, R^(1′) is NO₂ -   In some embodiments, R^(1′) is COC₁-C₆ alkyl. -   In some embodiments, R^(1′) is CO—C₆-C₁₀ aryl. -   In some embodiments, R^(1′) is CO(5- to 10-membered heteroaryl). -   In some embodiments, R^(1′) is CO₂C₁-C₆ alkyl. -   In some embodiments, R^(1′) is CO₂C₃-C₈ cycloalkyl. -   In some embodiments, R^(1′) is OCOC₁-C₆ alkyl. -   In some embodiments, R^(1′) is OCOC₆-C₁₀ aryl. -   In some embodiments, R^(1′) is OCO(5- to 10-membered heteroaryl). -   In some embodiments, R^(1′) is OCO(3- to 7-membered     heterocycloalkyl). -   In some embodiments, R^(1′) is C₆-C₁₀ aryl. -   In some embodiments, R^(1′) is phenyl. -   In some embodiments, R^(1′) is 5- to 10-membered heteroaryl. -   In some embodiments, R^(1′) is pyridyl (e.g., 4-pyridyl). -   In some embodiments, R^(1′) is pyrazolyl (e.g., 1-pyrazolyl). -   In some embodiments, R^(1′) is NH₂. -   In some embodiments, R^(1′) is NHC₁-C₆ alkyl. -   In some embodiments, R^(1′) is N(C₁-C₆ alkyl)₂. -   In some embodiments, R^(1′) is CONR⁸R⁹. -   In some embodiments, R^(1′) is SF₅. -   In some embodiments, R^(1′) is SC₁-C₆ alkyl, -   In some embodiments, R^(1′) is S(O₂)C₁-C₆ alkyl. -   In some embodiments, R^(1′) is S(O₂)CH₃. -   In some embodiments, R^(1′) is S(O₂)NR¹¹R¹². -   In some embodiments, R^(1′) is S(O₂)N(CH₃)₂. -   In some embodiments, R^(1′) is S(O)C₁-C₆ alkyl. -   In some embodiments, R^(1′) is S(O)CH₃. -   In some embodiments, R^(1′) is attached to a carbon of an aryl ring     A. -   In some embodiments, R^(1′) is attached to a carbon of a heteroaryl     ring A. -   In some embodiments, R^(1′) is attached to a nitrogen of a     heteroaryl ring A.

In some embodiments of any of the formulae herein, each of R¹ and R² is independently selected from the group consisting of C₁-C₆ alkyl optionally substituted with one or more hydroxy, halo, oxo, or C₁-C₆ alkoxy; C₃-C₇ cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C₁-C₆ alkoxy, or C₁-C₆ alkyl; wherein the C₁-C₆ alkoxy or C₁-C₆ alkyl is further optionally substituted with one to three hydroxy, halo, NR⁸R⁹, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, or C₁-C₆ alkyl wherein the C₁-C₆ alkoxy or C₁-C₆ alkyl is further optionally substituted with one to three hydroxy, halo, or oxo; C₁-C₆ haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; CO—C₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀ aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; S(O₂)NR¹¹R¹²; S(O)C₁-C₆ alkyl; and S(O₂)C₁-C₆ alkyl.

In some embodiments of any of the formulae herein, R¹ is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃; COCH₂CH₃; 2-methoxy-2-propyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O₂)CH₃, and S(O₂)NR¹¹R¹².

In some embodiments, R² is selected from the group consisting of fluoro, chloro, cyano, methyl; methoxy; ethoxy; isopropyl; 1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; COCH₃; COPh; 2-methoxy-2-propyl; S(O₂)CH₃, and S(O₂)NR¹¹R¹².

In some embodiments, one pair of R¹ and R² is on adjacent atoms, and taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino.

In some embodiments, the optionally substituted ring A is selected from the group consisting of a 5-membered heteroaryl comprising 2 or more heteroatoms, a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH, and NR¹, and a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the S(O)(NHR³)═N moiety; m is 1; n is 1; R¹ and R² are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is a pyrazolyl; m is 1; n is 1; R¹ and R² are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is an imidazolyl; m is 1; n is 1; R¹ and R² are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is a thiophenyl; m is 1; n is 1; R¹ and R² are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is a thiazolyl; m is 1; n is 1; R¹ and R² are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

wherein Z⁴ is selected from the group consisting of —CH₂—, —C(O)—, and NH; Z⁵ is selected from the group consisting of O, NH, N—CH₃, and —CH₂—.

The Variables o and p

-   In some embodiments, o=1 or 2. -   In some embodiments, o=1. -   In some embodiments, o=2. -   In some embodiments, p=0, 1, 2, or 3. -   In some embodiments, p=0. -   In some embodiments, p=1. -   In some embodiments, p=2. -   In some embodiments, o=1 and p=0. -   In some embodiments, o=2 and p=0. -   In some embodiments, o=1 and p=1. -   In some embodiments, o=1 and p=2. -   In some embodiments, o=2 and p=1. -   In some embodiments, o=2 and p=2. -   In some embodiments, o=2 and p=3.

The Ring B and Substitutions on the Ring B

-   In some embodiments, B is a 5- to 10-membered monocyclic or bicyclic     heteroaryl or a C₆-C₁₀ monocyclic or bicyclic aryl, such as phenyl. -   In some embodiments, B is a 5- to 6-membered monocyclic heteroaryl     or a C₆ monocyclic aryl. -   In some embodiments, B is a 5- to 10-membered monocyclic or bicyclic     heteroaryl. -   In some embodiments, B is a C₆-C₁₀ monocyclic or bicyclic aryl. -   In some embodiments, B is a 5-membered heteroaryl. -   In some embodiments, B is a 7-10 membered monocyclic or bicyclic     heteroaryl. -   In some embodiments, B is phenyl substituted with 1 or 2 R⁶ and     optionally substituted with 1, 2, or 3 R⁷. -   In some embodiments, B is pyridyl substituted with 1 or 2 R⁶ and     optionally substituted with 1, 2, or3 R⁷. -   In some embodiments, B is indazolyl substituted with 1 or 2 R⁶ and     optionally substituted with 1, 2, or3 R⁷. -   In some embodiments, B is pyrazolyl substituted with 1 or 2 R⁶ and     optionally substituted with 1 or 2R⁷. -   In some embodiments, B is phenyl, o is 1 or 2, and p is 0, 1, 2, or     3. -   In some embodiments, B is phenyl, o is 1, and p is 0, 1, 2, or 3. -   In some embodiments, B is phenyl, o is 2, and p is 0, 1, 2, or 3. -   In some embodiments, B is one of the rings disclosed hereinbelow,     substituted as disclosed hereinbelow, wherein in each case the bond     that is shown as being broken by the wavy line     connects B to the NH(CO)group of Formula AA.     In some embodiments, the substituted ring B

In some embodiments, the substituted ring B

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

In some embodiments, the substituted ring B is

The Groups R⁶ and R⁷

-   In some embodiments, -   R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl,     OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to     7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅,     S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl and 3- to 10-membered     heterocycloalkyl, and a C₂-C₆ alkenyl, -   wherein R⁶ and R⁷ are each optionally substituted with one or more     substituents independently selected from -   hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰,     COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀     aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl,     OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered     heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to     10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl),     NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein     the C₁-C₆ alkyl or C₁-C₆ alkoxy that R⁶ or R⁷ is substituted with is     optionally substituted with one or more hydroxyl, C₆-C₁₀ aryl or     NR⁸R⁹, or wherein R⁶ or R⁷ is optionally fused to a five- to     -seven-membered carbocyclic ring or heterocyclic ring containing one     or two heteroatoms independently selected from oxygen, sulfur and     nitrogen;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5-to 8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹. -   In some embodiments, -   R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl,     OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to     7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅,     S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl and 3- to 10-membered     heterocycloalkyl, and a C₂-C₆ alkenyl, -   wherein R⁶ and R⁷ are each optionally substituted with one or more     substituents independently selected from -   hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰,     COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀     aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl,     OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered     heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to     10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl),     NHCOC₂-C₆ alkynyl, -   C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or     C₁-C₆ alkoxy that R⁶ or R⁷ is substituted with is optionally     substituted with one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or     wherein R⁶ or R⁷ is optionally fused to a five- to -seven-membered     carbocyclic ring or heterocyclic ring containing one or two     heteroatoms independently selected from oxygen, sulfur and nitrogen;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₆ aliphatic carbocyclic ring or at least one 5-to 6-membered     heterocyclic ring containing 1 or 2 heteroatoms independently     selected from O, N, and S, wherein the carbocyclic ring or     heterocyclic ring is optionally independently substituted with one     or more substituents independently selected from hydroxy,     hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,     CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, -   R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl,     OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to     7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅,     SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to     7-membered heterocycloalkyl, -   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to     7-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹. -   In some embodiments, -   R⁶ and R⁷ are each independently selected from C₁-C₆ haloalkyl,     C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl,     CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl,     OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered     heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂,     NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl,     S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered     heterocycloalkyl, -   wherein the C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, and 3- to 7-membered     heterocycloalkyl is optionally substituted with one or more     substituents each independently selected from hydroxy, halo, CN,     oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹. -   In some embodiments, -   R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, halo,     CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀     aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered     heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂,     NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl,     S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered     heterocycloalkyl, -   wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered     heterocycloalkyl is optionally substituted with one or more     substituents each independently selected from hydroxy, halo, CN,     oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹. -   In some embodiments, -   R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl,     OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to     7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅,     SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to     7-membered heterocycloalkyl, -   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, and 3-     to 7-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are unsubstituted; -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹. -   In some embodiments, -   R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl,     OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to     7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅,     SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to     7-membered heterocycloalkyl, -   wherein the C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to 7-membered     heterocycloalkyl are each unsubstituted; -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹. -   In some embodiments, -   R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl,     C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀     aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4-     to 6-membered heterocycloalkyl, -   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to     6-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   and R⁷ is independently selected from C₁-C₆ alkyl, C₁-C₆         haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆         alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl,         OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to         7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered         heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and         4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is         optionally substituted with one to two C₁-C₆ alkoxy; -   or R⁶ and R⁷, taken together with the atoms connecting them,     independently form C₄-C₇ carbocyclic ring or at least one     5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms     independently selected from O, N, and S, wherein the carbocyclic     ring or heterocyclic ring is optionally independently substituted     with one or more substituents independently selected from hydroxy,     halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, -   R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆     alkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, C₆-C₁₀ aryl,     5- to 10-membered heteroaryl, CONR⁸R⁹, and 3- to 7-membered     heterocycloalkyl, -   wherein the C₁-C₆ alkyl and 3- to 7-membered heterocycloalkyl is     optionally substituted with one or more substituents each     independently selected from hydroxy or oxo, -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring, wherein the carbocyclic ring is optionally     independently substituted with one or more hydroxy or oxo. -   In some embodiments, -   R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆     alkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, C₆-C₁₀ aryl,     5- to 10-membered heteroaryl, CONR⁸R⁹, and 3- to 7-membered     heterocycloalkyl, -   wherein the C₁-C₆ alkyl and 3- to 7-membered heterocycloalkyl is     optionally substituted with one or more substituents each     independently selected from hydroxy or oxo, -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₆ aliphatic carbocyclic ring, wherein the carbocyclic ring is     optionally independently substituted with one or more hydroxy or     oxo. -   In some embodiments, -   R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆     alkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, C₆-C₁₀ aryl,     5- to 10-membered heteroaryl, CONR⁸R⁹, and 3- to 7-membered     heterocycloalkyl, -   wherein the C₁-C₆ alkyl and 3- to 7-membered heterocycloalkyl is     optionally substituted with one or more substituents each     independently selected from hydroxy or oxo, -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one 5-to     8-membered heterocyclic ring containing 1 or 2 heteroatoms     independently selected from O, N, and S, wherein the heterocyclic     ring is optionally independently substituted with one or more     hydroxy or oxo. -   In some embodiments, -   R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆     alkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, C₆-C₁₀ aryl,     5- to 10-membered heteroaryl, CONR⁸R⁹, and 3- to 7-membered     heterocycloalkyl, -   wherein the C₁-C₆ alkyl and 3- to 7-membered heterocycloalkyl is     optionally substituted with one or more substituents each     independently selected from hydroxy or oxo, -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring, wherein the carbocyclic ring is optionally     independently substituted with one or more hydroxy or oxo. -   In some embodiments, -   at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₆ aliphatic carbocyclic ring, wherein the carbocyclic ring is     optionally independently substituted with one or more hydroxy or     oxo. -   In some embodiments, -   at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one C₄     aliphatic carbocyclic ring, wherein the carbocyclic ring is     optionally independently substituted with one or more hydroxy or     oxo. -   In some embodiments, -   at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one C₅     aliphatic carbocyclic ring, wherein the carbocyclic ring is     optionally independently substituted with one or more hydroxy or     oxo. -   In some embodiments, -   at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one C₆     aliphatic carbocyclic ring, wherein the carbocyclic ring is     optionally independently substituted with one or more hydroxy or     oxo. -   In some embodiments, -   at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one 5-to     6-membered heterocyclic ring containing 1 heteroatom independently     selected from O, N, and S, wherein the heterocyclic ring is     optionally independently substituted with one or more hydroxy or     oxo. -   In some embodiments, -   at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     5-membered heterocyclic ring containing 1 heteroatom independently     selected from O, N, and S, wherein the heterocyclic ring is     optionally independently substituted with one or more hydroxy or     oxo. -   In some embodiments, -   at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     6-membered heterocyclic ring containing 1 heteroatom independently     selected from O, N, and S, wherein the heterocyclic ring is     optionally independently substituted with one or more hydroxy or     oxo. -   In some embodiments, -   at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one C₄     aliphatic carbocyclic ring, wherein the carbocyclic ring is     optionally independently substituted with one or more C₁-C₆ alkyl. -   In some embodiments, -   at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one C₅     aliphatic carbocyclic ring, wherein the carbocyclic ring is     optionally independently substituted with one or more C₁-C₆ alkyl. -   In some embodiments, -   at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one C₆     aliphatic carbocyclic ring, wherein the carbocyclic ring is     optionally independently substituted with one or more C₁-C₆ alkyl. -   In some embodiments, -   at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one 5-to     6-membered heterocyclic ring containing 1 heteroatom independently     selected from O, N, and S, wherein the heterocyclic ring is     optionally independently substituted with one or more C₁-C₆ alkyl. -   In some embodiments, -   at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     5-membered heterocyclic ring containing 1 heteroatom independently     selected from O, N, and S, wherein the heterocyclic ring is     optionally independently substituted with one or more C₁-C₆ alkyl. -   In some embodiments, -   at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     6-membered heterocyclic ring containing 1 heteroatom independently     selected from O, N, and S, wherein the heterocyclic ring is     optionally independently substituted with one or more C₁-C₆ alkyl. -   In some embodiments, o=1; p=0; and -   R⁶ is selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,     C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl,     CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl,     N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₇     cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆     alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to 7-membered     heterocycloalkyl is optionally substituted with one or more     substituents each independently selected from hydroxy, halo, CN,     oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl. -   In some embodiments, o=1; p=1; and -   R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆     alkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, C₆-C₁₀ aryl,     5- to 10-membered heteroaryl, CONR⁸R⁹, and 3- to 7-membered     heterocycloalkyl, -   wherein the C₁-C₆ alkyl and 3- to 7-membered heterocycloalkyl is     optionally substituted with one or more substituents each     independently selected from hydroxy or oxo, -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring, wherein the carbocyclic ring is optionally     independently substituted with one or more hydroxy or oxo. -   In some embodiments, o=1 or 2; p=1, 2, or 3; and -   R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆     alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl,     OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to     7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅,     SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 3- to     7-membered heterocycloalkyl, -   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, and 3-     to 7-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl. -   In some embodiments, o=2; p=1; and -   each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇     cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo,     CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl;     CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl, -   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to     6-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   and R⁷ is independently selected from C₁-C₆ alkyl, C₁-C₆         haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆         alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl,         OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to         7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered         heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and         4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is         optionally substituted with one to two C₁-C₆ alkoxy; -   or R⁶ and R⁷, taken together with the atoms connecting them,     independently form C₄-C₇ carbocyclic ring or at least one     5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms     independently selected from O, N, and S, wherein the carbocyclic     ring or heterocyclic ring is optionally independently substituted     with one or more substituents independently selected from hydroxy,     halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, o=2; p=2 or 3; and -   each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇     cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo,     CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl;     CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl, -   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to     6-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein each R⁷ is independently selected from C₁-C₆ alkyl,         C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN,         COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆         alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3-         to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered         heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and         4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is         optionally substituted with one to two C₁-C₆ alkoxy; -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₇ (e.g., C₄-C₆) carbocyclic ring (e.g., aliphatic carbocyclic     ring) or at least one 5-to-7-membered (e.g., 5-to-6-membered)     heterocyclic ring containing 1 or 2 heteroatoms independently     selected from O, N, and S, wherein the carbocyclic ring or     heterocyclic ring is optionally independently substituted with one     or more substituents independently selected from hydroxy,     hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,     CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, o=1 or 2; p=1, 2, or 3; and -   R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆     alkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, C₆-C₁₀ aryl,     5- to 10-membered heteroaryl, CONR⁸R⁹, and 3- to 7-membered     heterocycloalkyl, -   wherein the C₁-C₆ alkyl and 3- to 7-membered heterocycloalkyl is     optionally substituted with one or more substituents each     independently selected from hydroxy or oxo, -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₈ carbocyclic ring, wherein the carbocyclic ring is optionally     independently substituted with one or more hydroxy or oxo. -   In some embodiments, o=1 or 2; p=1, 2, or 3; and -   R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆     alkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, C₆-C₁₀ aryl,     5- to 10-membered heteroaryl, CONR⁸R⁹, and 3- to 7-membered     heterocycloalkyl, -   wherein the C₁-C₆ alkyl and 3- to 7-membered heterocycloalkyl is     optionally substituted with one or more substituents each     independently selected from hydroxy or oxo. -   In some embodiments, o=1 or 2; p=1, 2, or 3; and -   one R⁶ and one R⁷ are on adjacent atoms, and taken together with the     atoms connecting them, form a C₄-C₈ carbocyclic ring or a 5- to     8-membered heterocyclic ring containing 1 or 2 heteroatoms     independently selected from O, N, and S, wherein the carbocyclic     ring or heterocyclic ring is optionally independently substituted     with one or more substituents independently selected from hydroxy,     halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, o=1 or 2; p=1, 2, or 3; and -   one R⁶ and one R⁷ are on adjacent atoms, and taken together with the     atoms connecting them, form a C₆ carbocyclic ring or a     5-to-6-membered heterocyclic ring containing 1 or 2 heteroatoms     independently selected from O, N, and S, wherein the carbocyclic     ring or heterocyclic ring is optionally independently substituted     with one or more substituents independently selected from hydroxy,     halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, o=1 or 2; p=1, 2, or 3; and -   one R⁶ and one R⁷ are on adjacent atoms, and taken together with the     atoms connecting them, form a C₄-C₈ carbocyclic ring or a 5- to     8-membered heterocyclic ring containing 1 or 2 heteroatoms     independently selected from O, N, and S, wherein the carbocyclic     ring or heterocyclic ring is unsubstituted. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and     each pair of one R⁶ and one R⁷ taken together with the atoms     connecting them independently form a C₄-C₈ carbocyclic ring or a 5-     to 8-membered heterocyclic ring containing 1 or 2 heteroatoms     independently selected from O, N, and S, wherein each carbocyclic     ring or heterocyclic ring is optionally independently substituted     with one or more substituents independently selected from hydroxy,     halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and     each pair of one R⁶ and one R⁷ taken together with the atoms     connecting them independently form a C₆ carbocyclic ring or a 5-     to-6-membered heterocyclic ring containing 1 or 2 heteroatoms     independently selected from O, N, and S, wherein the carbocyclic     ring or heterocyclic ring is optionally independently substituted     with one or more substituents independently selected from hydroxy,     halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and     each pair of one R⁶ and one R⁷ taken together with the atoms     connecting them independently form a C₅ carbocyclic ring, wherein     the carbocyclic ring is optionally independently substituted with     one or more substituents independently selected from hydroxy, halo,     oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and     each pair of one R⁶ and one R⁷ taken together with the atoms     connecting them independently form a C₄ carbocyclic ring, wherein     the carbocyclic ring is optionally independently substituted with     one or more substituents independently selected from hydroxy, halo,     oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl,     and CONR⁸R⁹. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, one     pair of one R⁶ and one R⁷ taken together with the atoms connecting     them independently form a C₄ carbocyclic ring, and the other pair of     one R⁶ and one R⁷ taken together with the atoms connecting them     independently form a C₅ carbocyclic ring, wherein each of C₄ and C₅     carbocyclic ring is optionally independently substituted with one or     more substituents independently selected from hydroxy, halo, oxo,     C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, one     pair of one R⁶ and one R⁷ taken together with the atoms connecting     them independently form a C₅ carbocyclic ring, and the other pair of     one R⁶ and one R⁷ taken together with the atoms connecting them     independently form a 5- to 8-membered heterocyclic ring containing 1     or 2 heteroatoms independently selected from O, N, and S (e.g., a     5-membered heteorocyclic ring, e.g., 5-membered heterocyclic ring     containing 1 heteroatom), wherein each of carbocyclic and     heterocyclic ring is optionally independently substituted with one     or more substituents independently selected from hydroxy, halo, oxo,     C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and     each pair of one R⁶ and one R⁷ taken together with the atoms     connecting them independently form a C₄-C₈ carbocyclic ring or a 5-     to 8-membered heterocyclic ring containing 1 or 2 heteroatoms     independently selected from O, N, and S, wherein the carbocyclic     ring or heterocyclic ring is unsubstituted.

Particular Embodiments wherein o=1; p=0

-   In some embodiments, R⁶ is C₁-C₆ alkyl. -   In some embodiments, R⁶ is isopropyl. -   In some embodiments, R⁶ is ethyl. -   In some embodiments, R⁶ is methyl. -   In some embodiments, R⁶ is C₁-C₆ alkyl substituted with one or more     halo. -   In some embodiments, R⁶ is trifluoromethyl. -   In some embodiments, R⁶ is trifluoromethoxy. -   In some embodiments, R⁶ is C₃-C₇ cycloalkyl. -   In some embodiments, R⁶ is cyclopropyl. -   In some embodiments, R⁶ is halo. -   In some embodiments, R⁶ is chloro. -   In some embodiments, R⁶ is fluoro. -   In some embodiments, R⁶ is cyano. -   In some embodiments, R⁶ is attached to a carbon of an aryl ring B. -   In some embodiments, R⁶ is attached to a carbon of a heteroaryl ring     B. -   In some embodiments, R⁶ is attached to a nitrogen of a heteroaryl     ring B.

Particular Embodiments wherein o=1 or 2; p=1, 2, or 3

-   In some embodiments, at least one R⁶ is C₁-C₆ alkyl, and at least     one R⁷ is C₁-C₆ alkyl optionally substituted with one or more halo. -   In some embodiments, at least one R⁶ is C₁-C₆ alkyl and at least one     R⁷ is C₁-C₆ alkyl. -   In some embodiments, at least one R⁶ is isopropyl and at least one     R⁷ is methyl. -   In some embodiments, at least one R⁶ is isopropyl and at least one     R⁷ is isopropyl. -   In some embodiments, o=1; p=1; R⁶ is isopropyl; and R⁷ is isopropyl. -   In some embodiments, at least one R⁶ is C₁-C₆ alkyl, and at least     one R⁷ is C₁-C₆ alkyl substituted with one or more halo. -   In some embodiments, at least one R⁶ is isopropyl and at least one     R⁷ is trifluoromethyl. -   In some embodiments, at least one R⁶ is C₁-C₆ alkyl, and at least     one R⁷ is C₃-C₇ cycloalkyl. -   In some embodiments, at least one R⁶ is isopropyl and at least one     R⁷ is cyclopropyl. -   In some embodiments, o=1; p=1; R⁶ is isopropyl; and R⁷ is     cyclopropyl. -   In some embodiments, at least one R⁶ is C₁-C₆ alkyl, and at least     one R⁷ is halo. -   In some embodiments, at least one R⁶ is isopropyl and at least one     R⁷ is halo. -   In some embodiments, at least one R⁶ is isopropyl and at least one     R⁷ is chloro. -   In some embodiments, at least one R⁶ is isopropyl and at least one     R⁷ is fluoro. -   In some embodiments, o=1; p=1; R⁶ is isopropyl; and R⁷ is chloro. -   In some embodiments, o=2; p=1; at least one R⁶ is isopropyl; and R⁷     is chloro. -   In some embodiments, o=1; p=1; R⁶ is isopropyl; and R⁷ is fluoro. -   In some embodiments, o=2; p=1; at least one R⁶ is isopropyl; and R⁷     is fluoro. -   In some embodiments, o=2; p=2; at least one R⁶ is isopropyl; and at     least one R⁷ is fluoro. -   In some embodiments, o=2; p=2; at least one R⁶ is isopropyl; one R⁷     is fluoro; and the other R⁷ is cyano. -   In some embodiments, o=2; p=3; at least one R⁶ is isopropyl; two R⁷     are fluoro; and one R⁷ is chloro. -   In some embodiments, o=2; p=1; at least one R⁶ is ethyl; and R⁷ is     fluoro. -   In some embodiments, o=2; p=1; one R⁶ is isopropyl; the other R⁶ is     trifluoromethyl; and R⁷ is chloro. -   In some embodiments, at least one R⁶ is C₁-C₆ alkyl, and at least     one R⁷ is cyano. -   In some embodiments, at least one R⁶ is isopropyl and at least one     R⁷ is cyano. -   In some embodiments, o=1; p=1; R⁶ is isopropyl; and R⁷ is cyano. -   In some embodiments, o=2; p=1; at least one R⁶ is isopropyl; and R⁷     is cyano. -   In some embodiments, at least one R⁶ is C₃-C₇ cycloalkyl, and at     least one R⁷ is C₃-C₇ cycloalkyl. -   In some embodiments, at least one R⁶ is cyclopropyl, and at least     one R⁷ is cyclopropyl. -   In some embodiments, at least one R⁶ is C₃-C₇ cycloalkyl, and at     least one R⁷ is halo. -   In some embodiments, at least one R⁶ is cyclopropyl and at least one     R⁷ is halo. -   In some embodiments, at least one R⁶ is cyclopropyl and at least one     R⁷ is chloro. -   In some embodiments, at least one R⁶ is cyclopropyl and at least one     R⁷ is fluoro. -   In some embodiments, o=1; p=1; R⁶ is cyclopropyl; and R⁷ is chloro. -   In some embodiments, o=1; p=1; R⁶ is cyclopropyl; and R⁷ is fluoro. -   In some embodiments, at least one R⁶ is C₁-C₆ alkyl, and at least     one R⁷ is C₁-C₆ alkoxy optionally substituted with one or more halo. -   In some embodiments, at least one R⁶ is isopropyl, and at least one     R⁷ is C₁-C₆ alkoxy. -   In some embodiments, at least one R⁶ is isopropyl, and at least one     R⁷ is methoxy. -   In some embodiments, o=1; p=1; R⁶ is isopropyl, and R⁷ is methoxy. -   In some embodiments, o=2; p=1; at least one R⁶ is isopropyl, and R⁷     is methoxy. -   In some embodiments, at least one R⁶ is C₁-C₆ alkyl, and at least     one R⁷ is C₁-C₆ alkoxy substituted with one or more halo. -   In some embodiments, at least one R⁶ is isopropyl, and at least one     R⁷ is trifluoromethoxy. -   In some embodiments, at least one R⁶ is isopropyl, and at least one     R⁷ is difluoromethoxy. -   In some embodiments, at least one R⁶ is halo, and at least one R⁷ is     C₁-C₆ haloalkyl optionally substituted with hydroxy. -   In some embodiments, o=1; p=1; R⁶ is chloro, and R⁷ is     trifluoromethyl. -   In some embodiments, at least one R⁶ is halo, and at least one R⁷ is     C₁-C₆ haloalkoxy. -   In some embodiments, at least one R⁶ is chloro, and at least one R⁷     is trifluoromethoxy. -   In some embodiments, o=1; p=1; R⁶ is chloro, and R⁷ is     trifluoromethoxy. -   In some embodiments, at least one R⁶ is C₁-C₆ alkoxy; and at least     one R⁷ is halo. -   In some embodiments, o=1; p=2; R⁶ is C₁-C₆ alkoxy; and at least one     R⁷ is chloro. -   In some embodiments, at least one R⁷ is C₁-C₆ alkyl, and at least     one R⁶ is C₁-C₆ alkyl optionally substituted with one or more halo. -   In some embodiments, at least one R⁷ is isopropyl and at least one     R⁶ is methyl. -   In some embodiments, at least one R⁷ is C₁-C₆ alkyl, and at least     one R⁶ is C₁-C₆ alkyl substituted with one or more halo. -   In some embodiments, at least one R⁷ is isopropyl and at least one     R⁶ is trifluoromethyl. -   In some embodiments, at least one R⁷ is C₁-C₆ alkyl, and at least     one R⁶ is C₃-C₇ cycloalkyl. -   In some embodiments, at least one R⁷ is isopropyl and at least one     R⁶ is cyclopropyl. -   In some embodiments, o=1; p=1; R⁷ is isopropyl; and R⁶ is     cyclopropyl. -   In some embodiments, at least one R⁷ is C₁-C₆ alkyl, and at least     one R⁶ is halo. -   In some embodiments, at least one R⁷ is isopropyl and at least one     R⁶ is halo. -   In some embodiments, at least one R⁷ is isopropyl and at least one     R⁶ is chloro. -   In some embodiments, at least one R⁷ is isopropyl and at least one     R⁶ is fluoro. -   In some embodiments, o=1; p=1; R⁷ is isopropyl; and R⁶ is chloro. -   In some embodiments, o=2; p=1; R⁷ is isopropyl; and at least one R⁶     is chloro. -   In some embodiments, o=1; p=1; R⁷ is isopropyl; and R⁶ is fluoro. -   In some embodiments, o=2; p=1; R⁷ is isopropyl; and at least one R⁶     is fluoro. -   In some embodiments, o=2; p=2; R⁷ is isopropyl; and at least one R⁶     is fluoro. -   In some embodiments, o=2; p=2; at least one R⁷ is isopropyl; one R⁶     is fluoro; and the other R⁶ is cyano. -   In some embodiments, o=2; p=1; R⁷ is ethyl; and at least one R⁶ is     fluoro. -   In some embodiments, o=1; p=2; one R⁷ is isopropyl; the other R⁷ is     trifluoromethyl; and R⁶ is chloro. -   In some embodiments, at least one R⁷ is C₁-C₆ alkyl, and at least     one R⁶ is cyano. -   In some embodiments, at least one R⁷ is isopropyl and at least one     R⁶ is cyano. -   In some embodiments, o=1; p=1; R⁷ is isopropyl; and R⁶ is cyano. -   In some embodiments, o=2; p=1; R⁷ is isopropyl; and at least one R⁶     is cyano. -   In some embodiments, at least one R⁷ is C₃-C₇ cycloalkyl, and at     least one R⁶ is C₃-C₇ cycloalkyl. -   In some embodiments, at least one R⁷ is cyclopropyl, and at least     one R⁶ is cyclopropyl. -   In some embodiments, at least one R⁷ is C₃-C₇ cycloalkyl, and at     least one R⁶ is halo. -   In some embodiments, at least one R⁷ is cyclopropyl and at least one     R⁶ is halo. -   In some embodiments, at least one R⁷ is cyclopropyl and at least one     R⁶ is chloro. -   In some embodiments, at least one R⁷ is cyclopropyl and at least one     R⁶ is fluoro. -   In some embodiments, o=1; p=1; R⁷ is cyclopropyl; and R⁶ is chloro. -   In some embodiments, o=1; p=1; R⁷ is cyclopropyl; and R⁶ is fluoro. -   In some embodiments, at least one R⁷ is C₁-C₆ alkyl, and at least     one R⁶ is C₁-C₆ alkoxy optionally substituted with one or more halo. -   In some embodiments, at least one R⁷ is isopropyl, and at least one     R⁶ is C₁-C₆ alkoxy. -   In some embodiments, at least one R⁷ is isopropyl, and at least one     R⁶ is methoxy. -   In some embodiments, o=1; p=1; R⁷ is isopropyl, and R⁶ is methoxy. -   In some embodiments, o=2; p=1; R⁷ is isopropyl, and at least one R⁶     is methoxy. -   In some embodiments, at least one R⁷ is C₁-C₆ alkyl, and at least     one R⁶ is C₁-C₆ alkoxy substituted with one or more halo. -   In some embodiments, at least one R⁷ is isopropyl, and at least one     R⁶ is trifluoromethoxy. -   In some embodiments, at least one R⁷ is halo, and at least one R⁶ is     C₁-C₆ haloalkyl optionally substituted with one or more hydroxy. -   In some embodiments, o=1; p=1; R⁷ is chloro, and R⁶ is     trifluoromethyl. -   In some embodiments, at least one R⁷ is halo, and at least one R⁶ is     C₁-C₆ haloalkoxy. -   In some embodiments, at least one R⁷ is chloro, and at least one R⁶     is trifluoromethoxy. -   In some embodiments, o=1; p=1; R⁷ is chloro, and R⁶ is     trifluoromethoxy. -   In some embodiments, at least one R⁷ is C₁-C₆ alkoxy; and at least     one R⁶ is halo. -   In some embodiments, o=1; p=2; at least one R⁷ is C₁-C₆ alkoxy; and     R⁶ is chloro. -   In some embodiments, R⁶ and R⁷ are each attached to a carbon of an     aryl ring B. -   In some embodiments, R⁶ and R⁷ are each attached to a carbon of a     heteroaryl ring B. -   In some embodiments, R⁶ is attached to a carbon and R⁷ is attached     to a nitrogen of a heteroaryl ring B. -   In some embodiments, R⁷ is attached to a carbon and R⁶ is attached     to a nitrogen of a heteroaryl ring B. -   In some embodiments, one R⁶ and one R⁷ are on adjacent atoms, and     taken together with the atoms connecting them, form a C₅ carbocyclic     ring optionally substituted with one or more substituents     independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆     alkoxy, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, R⁶ and R⁷ are on adjacent atoms, and taken     together with the atoms connecting them, form a C₅ aliphatic     carbocyclic ring. -   In some embodiments, R⁶ and R⁷ are on adjacent atoms, and taken     together with the atoms connecting them, form a C₆ carbocyclic ring     optionally substituted with one or more substituents independently     selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,     ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, R⁶ and R⁷ are on adjacent atoms, and taken     together with the atoms connecting them, form a C₆ aliphatic     carbocyclic ring. -   In some embodiments, R⁶ and R⁷ are on adjacent atoms, and taken     together with the atoms connecting them, form a C⁶ aromatic     carbocyclic ring. -   In some embodiments, R⁶ and R⁷ are on adjacent atoms, and taken     together with the atoms connecting them, form a 5-membered     heterocyclic ring containing 1 or 2 heteroatoms independently     selected from O, N, and S, optionally substituted with one or more     substituents independently selected from hydroxy, halo, oxo, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and     CONR⁸R⁹. -   In some embodiments, R⁶ and R⁷ are on adjacent atoms, and taken     together with the atoms connecting them, form a 5-membered aliphatic     heterocyclic ring containing 1 or 2 heteroatoms independently     selected from O, N, and S. -   In some embodiments, R⁶ and R⁷ are on adjacent atoms, and taken     together with the atoms connecting them, form a 5-membered     heteroaromatic ring containing 1 or 2 heteroatoms independently     selected from O, N, and S. -   In some embodiments, R⁶ and R⁷ are on adjacent atoms, and taken     together with the atoms connecting them, form a 6-membered     heterocyclic ring containing 1 or 2 heteroatoms independently     selected from O, N, and S, optionally substituted with one or more     substituents independently selected from hydroxy, halo, oxo, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and     CONR⁸R⁹. -   In some embodiments, R⁶ and R⁷ are on adjacent atoms, and taken     together with the atoms connecting them, form a 6-membered aliphatic     heterocyclic ring containing 1 or 2 heteroatoms independently     selected from O, N, and S. -   In some embodiments, R⁶ and R⁷ are on adjacent atoms, and taken     together with the atoms connecting them, form a 6-membered     heteroaromatic ring containing 1 or 2 heteroatoms independently     selected from O, N, and S. -   In some embodiments, one R⁶ and one R⁷ are on adjacent atoms, and     taken together with the atoms connecting them, form a C₄-C₈     carbocyclic ring or a 5- to 8-membered heterocyclic ring containing     1 or 2 heteroatoms independently selected from O, N, and S, -   wherein the ring is fused to the B ring at the 2- and 3-positions     relative to the bond connecting the B ring to the NH(CO)group. -   In some embodiments, o=1; p=2; and -   one pair of one R⁶ and one R⁷, are on adjacent atoms; and said pair     of one R⁶ and one R⁷ taken together with the atoms connecting them     form form a C₄-C₈ carbocyclic ring or a 5- to 8-membered     heterocyclic ring containing 1 or 2 heteroatoms independently     selected from O, N, and S, -   wherein the ring is fused to the B ring at the 2- and 3-positions     relative to the bond connecting the B ring to the NR³(CO) group. -   In some embodiments, o=1; p=2; and -   one pair of one R⁶ and one R⁷, are on adjacent atoms; and said pair     of one R⁶ and one R⁷ taken together with the atoms connecting them     form form a C₄-C₈ carbocyclic ring optionally independently     substituted with one or more substituents independently selected     from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰,     COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, o=1; p=2; and -   one pair of one R⁶ and one R⁷, are on adjacent atoms; and said pair     of one R⁶ and one R⁷ taken together with the atoms connecting them     form form a C₅ carbocyclic ring optionally independently substituted     with one or more substituents independently selected from hydroxy,     halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, o=1; p=2; and -   one pair of one R⁶ and one R⁷, are on adjacent atoms; and said pair     of one R⁶ and one R⁷ taken together with the atoms connecting them     form form a C₅ aliphatic carbocyclic ring. -   In some embodiments, o=2; p=2; and -   one pair of one R⁶ and one R⁷, are on adjacent atoms; and said pair     of one R⁶ and one R⁷ taken together with the atoms connecting them     form form a C₄-C₈ carbocyclic ring optionally independently     substituted with one or more substituents independently selected     from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰,     COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, o=2; p=2; and -   one pair of one R⁶ and one R⁷, are on adjacent atoms; and said pair     of one R⁶ and one R⁷ taken together with the atoms connecting them     form form a C₅ carbocyclic ring optionally independently substituted     with one or more substituents independently selected from hydroxy,     halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, o=1; p=2; and -   one pair of one R⁶ and one R⁷, are on adjacent atoms; and said pair     of one R⁶ and one R⁷ taken together with the atoms connecting them     form form a C₅ aliphatic carbocyclic ring. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms; one     pair of one R⁶ and one R⁷ taken together with the atoms connecting     them form a C₄ carbocyclic ring optionally independently substituted     with one or more substituents independently selected from hydroxy,     halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     C₆-C₁₀ aryl, and CONR⁸R⁹; and the other pair of one R⁶ and one R⁷     taken together with the atoms connecting them form a C₅ carbocyclic     ring optionally independently substituted with one or more     substituents independently selected from hydroxy, halo, oxo, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and     CONR⁸R⁹. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms; one     pair of one R⁶ and one R⁷ taken together with the atoms connecting     them form a C₄ aliphatic carbocyclic ring and the other pair of one     R⁶ and one R⁷ taken together with the atoms connecting them form a     C₅ aliphatic carbocyclic ring. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and     each pair of one R⁶ and one R⁷ taken together with the atoms     connecting them form a C₅ carbocyclic ring optionally independently     substituted with one or more substituents independently selected     from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰,     COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and     each pair of one R⁶ and one R⁷ taken together with the atoms     connecting them form a C₅ aliphatic carbocyclic ring. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and     each pair of one R⁶ and one R⁷ taken together with the atoms     connecting them form a C₆ carbocyclic ring optionally independently     substituted with one or more substituents independently selected     from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰,     COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and     each pair of one R⁶ and one R⁷ taken together with the atoms     connecting them form a C₆ aliphatic carbocyclic ring. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and     each pair of one R⁶ and one R⁷ taken together with the atoms     connecting them form a C₆ aromatic carbocyclic ring. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and     each pair of one R⁶ and one R⁷ taken together with the atoms     connecting them form a 5-membered heterocyclic ring containing 1 or     2 heteroatoms independently selected from O, N, and S, optionally     substituted with one or more substituents independently selected     from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰,     COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and     each pair of one R⁶ and one R⁷ taken together with the atoms     connecting them form a 5-membered aliphatic heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and     each pair of one R⁶ and one R⁷ taken together with the atoms     connecting them form a 5-membered heteroaromatic ring containing 1     or 2 heteroatoms independently selected from O, N, and S. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and     each pair of one R⁶ and one R⁷ taken together with the atoms     connecting them form a 6-membered heterocyclic ring containing 1 or     2 heteroatoms independently selected from O, N, and S, optionally     substituted with one or more substituents independently selected     from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰,     COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and     each pair of one R⁶ and one R⁷ taken together with the atoms     connecting them form a 6-membered aliphatic heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and     each pair of one R⁶ and one R⁷ taken together with the atoms     connecting them form a 6-membered heteroaromatic ring containing 1     or 2 heteroatoms independently selected from O, N, and S. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms; one     pair of one R⁶ and one R⁷ taken together with the atoms connecting     them form a C₄₋₈ carbocyclic ring optionally independently     substituted with one or more substituents independently selected     from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰,     COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; and the other pair of one     R⁶ and one R⁷ taken together with the atoms connecting them form a     5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms     independently selected from O, N, and S, optionally substituted with     one or more substituents independently selected from hydroxy, halo,     oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms; one     pair of one R⁶ and one R⁷ taken together with the atoms connecting     them form a C₅ aliphatic carbocyclic ring and the other pair of one     R⁶ and one R⁷ taken together with the atoms connecting them form a     5-membered aliphatic heterocyclic ring containing 1 or 2 heteroatoms     independently selected from O, N, and S. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms; one     pair of one R⁶ and one R⁷ taken together with the atoms connecting     them form a C₅ carbocyclic ring optionally independently substituted     with one or more substituents independently selected from hydroxy,     halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     C₆-C₁₀ aryl, and CONR⁸R⁹; and the other pair of one R⁶ and one R⁷     taken together with the atoms connecting them form a 6-membered     heterocyclic ring containing 1 or 2 heteroatoms independently     selected from O, N, and S, optionally substituted with one or more     substituents independently selected from hydroxy, halo, oxo, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and     CONR⁸R⁹. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms; one     pair of one R⁶ and one R⁷ taken together with the atoms connecting     them form a C₅ aliphatic carbocyclic ring and the other pair of one     R⁶ and one R⁷ taken together with the atoms connecting them form a     5-membered aliphatic heterocyclic ring containing 1 or 2 heteroatoms     independently selected from O, N, and S. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and     each pair of one R⁶ and one R⁷ taken together with the atoms     connecting them independently form a C₄-C₈ carbocyclic ring or a 5-     to 8-membered heterocyclic ring containing 1 or 2 heteroatoms     independently selected from O, N, and S, -   wherein one of the two rings is fused to the B ring at the 2- and     3-positions relative to the bond connecting the B ring to the     NR³(CO) group, and the other of the two rings is fused to the B ring     at the 5- and 6-positions relative to the bond connecting the B ring     to the NH(CO) group. -   In some embodiments, o=2; p=2 or 3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and     each pair of one R⁶ and one R⁷ taken together with the atoms     connecting them independently form a C₄-C₈ carbocyclic ring or a 5-     to 8-membered heterocyclic ring containing 1 or 2 heteroatoms     independently selected from O, N, and S, -   wherein one of the two rings is fused to the B ring at the 2- and     3-positions relative to the bond connecting the B ring to the     NR³(CO) group, and the other of the two rings is fused to the B ring     at the 4- and 5-positions relative to the bond connecting the B ring     to the NH(CO) group. -   In some embodiments, o=2; p=2; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and     each pair of one R⁶ and one R⁷ taken together with the atoms     connecting them form a C₅ aliphatic carbocyclic ring. -   In some embodiments, o=2; p=2; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, one     pair of one R⁶ and one R⁷ taken together with the atoms connecting     them form a C₄ aliphatic carbocyclic ring, and the other pair of one     R⁶ and one R⁷ taken together with the atoms connecting them form a     C₅ aliphatic carbocyclic ring. -   In some embodiments, o=2; p=2; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and     each pair of one R⁶ and one R⁷ taken together with the atoms     connecting them form a C₄ aliphatic carbocyclic ring. -   In some embodiments, o=2; p=2; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, one     pair of one R⁶ and one R⁷ taken together with the atoms connecting     them form a C₅ aliphatic carbocyclic ring, and the other pair of one     R⁶ and one R⁷ taken together with the atoms connecting them form a     5-membered heterocyclic ring containing 1 or 2 heteroatoms     independently selected from O, N, and S. -   In some embodiments, o=2; p=3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and     each pair of one R⁶ and one R⁷ taken together with the atoms     connecting them form a C₅ aliphatic carbocyclic ring; and one R⁷ is     halo (e.g., Cl or F). -   In some embodiments, o=2; p=3; and -   two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and     each pair of one R⁶ and one R⁷ taken together with the atoms     connecting them form a C₅ aliphatic carbocyclic ring; and one R⁷ is     CN. -   In some embodiments, one R⁷ is pyrazolyl and is para to the bond     connecting the B ring to the NH(CO) group of Formula AA. -   In some embodiments, one R⁷ is 3-pyrazolyl and is para to the bond     connecting the B ring to the NH(CO) group of Formula AA. -   In some embodiments, one R⁷ is 4-pyrazolyl and is para to the bond     connecting the B ring to the NH(CO) group of Formula AA. -   In some embodiments, one R⁷ is 5-pyrazolyl and is para to the bond     connecting the B ring to the NH(CO) group of Formula AA. -   In some embodiments, one R⁷ is thiazolyl and is para to the bond     connecting the B ring to the NH(CO) group of Formula AA.

In some embodiments, one R⁷ is 4-thiazolyl and is para to the bond connecting the B ring to the NH(CO) group of Formula AA.

-   In some embodiments, one R⁷ is 5-thiazolyl and is para to the bond     connecting the B ring to the NH(CO) group of Formula AA. -   In some embodiments, one R⁷ is furyl and is para to the bond     connecting the B ring to the NH(CO) group of Formula AA. -   In some embodiments, one R⁷ is 2-furyl and is para to the bond     connecting the B ring to the NH(CO) group of Formula AA. -   In some embodiments, one R⁷ is thiophenyl and is para to the bond     connecting the B ring to the NH(CO) group of Formula AA. -   In some embodiments, one R⁷ is 2-thiophenyl and is para to the bond     connecting the B ring to the NH(CO) group of Formula AA. -   In some embodiments, one R⁷ is phenyl and is para to the bond     connecting the B ring to the NH(CO) group of Formula AA. -   In some embodiments, one R⁷ is cycloalkenyl (e.g., cyclopentenyl,     e.g., 1-cyclopentenyl) and is para to the bond connecting the B ring     to the NR³(CO) group of Formula AA. -   In some embodiments, one R⁷ is phenyl optionally substituted with     one or more C₁-C₆ alkyl (e.g., methyl or propyl, e.g., 2-propyl)     optionally substituted with one or more hydroxyl, NR⁸R⁹ (e.g.,     dimethylamino), or C₆-C₁₀ aryl (e.g., phenyl, naphthyl, or     methylenedioxyphenyl and is para to the bond connecting the B ring     to the NH(CO) group of Formula AA.

In some embodiments, one R⁷ is phenyl optionally substituted with one or more C₁-C₆ alkoxy (e.g., methoxy) optionally substituted with one or more hydroxyl, NR⁸R⁹ (e.g., dimethylamino), or C₆-C₁₀ aryl (e.g., phenyl, naphthyl, or methylenedioxyphenyl and is para to the bond connecting the B ring to the NH(CO) group of Formula AA.

-   In some embodiments, one R⁷ is phenyl optionally substituted with     one or more C₆-C₁₀ aryloxy (e.g., phenoxy) and is para to the bond     connecting the B ring to the NH(CO) group of Formula AA. -   In some embodiments, one R⁷ is phenyl optionally substituted with     one or more CN and is para to the bond connecting the B ring to the     NH(CO) group of Formula AA. -   In some embodiments, one R⁷ is phenyl optionally substituted with     one or more halo (e.g., F, Cl) and is para to the bond connecting     the B ring to the NH(CO) group of Formula AA and is para to the bond     connecting the B ring to the NH(CO) group of Formula AA. -   In some embodiments, one R⁷ is phenyl optionally substituted with     one or more COOC₁-C₆ alkyl (e.g., CO₂t-Bu) and is para to the bond     connecting the B ring to the NH(CO) group of Formula AA. -   In some embodiments, one R⁷ is phenyl optionally substituted with     one or more S(O₂)C₁-C₆ alkyl (e.g., S(O₂)methyl) and is para to the     bond connecting the B ring to the NH(CO) group of Formula AA. -   In some embodiments, one R⁷ is phenyl optionally substituted with     one or more 3- to 7-membered heterocycloalkyl (e.g., morpholinyl)     and is para to the bond connecting the B ring to the NH(CO) group of     Formula AA. -   In some embodiments, one R⁷ is phenyl optionally substituted with     one or more CONR⁸R⁹ (e.g., unsubstituted amido) and is para to the     bond connecting the B ring to the NH(CO) group of Formula AA. -   In some embodiments, one R⁷ is phenyl optionally substituted with     one or more C₁-C₆ alkyl (e.g., methyl or propyl, e.g., 2-propyl) and     with one or more halo (e.g., F, Cl) and is para to the bond     connecting the B ring to the NH(CO) group of Formula AA and is para     to the bond connecting the B ring to the NH(CO) group of Formula AA. -   In some embodiments, R⁶ and R⁷ are each attached to a carbon of an     aryl ring B. -   In some embodiments, R⁶ and R⁷ are each attached to a carbon of a     heteroaryl ring B. -   In some embodiments, R⁶ is attached to a carbon and R⁷ is attached     to a nitrogen of a heteroaryl ring B. -   In some embodiments, R⁷ is attached to a carbon and R⁶ is attached     to a nitrogen of a heteroaryl ring B. -   In some embodiments, R⁶ and R⁷ are each independently selected from     a C₂-C₆ alkyl, C₂-C₆ haloalkyl, C₂-C₆ alkoxy, C₁-C₆ haloalkoxy, I,     CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl,     OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl),     OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,     CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, and     3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl, -   wherein R⁶ and R⁷ are each optionally substituted with one or more     substituents independently selected from hydroxy, halo, CN, oxo,     C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3-     to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered     heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆     alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3-     to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy,     and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy     that R⁶ or R⁷ is substituted with is optionally substituted with one     or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is     optionally fused to a five- to -seven-membered carbocyclic ring or     heterocyclic ring containing one or two heteroatoms independently     selected from oxygen, sulfur and nitrogen;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl), and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or one pair of R⁶ and R⁷ on adjacent atoms, taken together with the     atoms connecting them, independently form at least one C₄-C₈     carbocyclic ring or at least one 5- to 8-membered heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S, wherein the carbocyclic ring or heterocyclic ring is optionally     independently substituted with one or more substituents     independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹. -   In some embodiments, R⁶ and R⁷ are each independently selected from     a C₂-C₆ alkyl, C₂-C₆ haloalkyl, C₂-C₆ alkoxy, C₁-C₆ haloalkoxy, I,     CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl,     OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl),     OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,     CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl and     3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl, -   wherein R⁶ and R⁷ are each optionally substituted with one or more     substituents independently selected from hydroxy, halo, CN, oxo,     C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3-     to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered     heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆     alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3-     to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy,     and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy     that R⁶ or R⁷ is substituted with is optionally substituted with one     or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is     optionally fused to a five- to -seven-membered carbocyclic ring or     heterocyclic ring containing one or two heteroatoms independently     selected from oxygen, sulfur and nitrogen;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or one pair of R⁶ and R⁷ on adjacent atoms, taken together with the     atoms connecting them, independently form at least one C₄-C₈     carbocyclic ring or at least one 5- to 8-membered heterocyclic ring     containing 1 or 2 heteroatoms and/or heteroatomic groups     independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, wherein     the selected heteroatoms and/or heteroatomic groups are cumulative     with the nitrogen atoms present in ring B, and wherein the     carbocyclic ring or heterocyclic ring is optionally independently     substituted with one or more substituents independently selected     from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy,     NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, R⁶ and R⁷ are each independently selected from a C₂-C₆ alkyl, C₂-C₆ haloalkyl, C₁-C₆ haloalkoxy, I, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl,

-   wherein R⁶ and R⁷ are each optionally substituted with one or more     substituents independently selected from hydroxy, halo, CN, oxo,     C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3-     to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered     heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆     alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3-     to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy,     and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy     that R⁶ or R⁷ is substituted with is optionally substituted with one     or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is     optionally fused to a five- to -seven-membered carbocyclic ring or     heterocyclic ring containing one or two heteroatoms independently     selected from oxygen, sulfur and nitrogen;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or one pair of R⁶ and R⁷ on adjacent atoms, taken together with the     atoms connecting them, independently form at least one C₄-C₈     carbocyclic ring or at least one 5- to 8-membered heterocyclic ring     containing 1 or 2 heteroatoms and/or heteroatomic groups     independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, wherein     the selected heteroatoms and/or heteroatomic groups are cumulative     with the nitrogen atoms present in ring B, and wherein the     carbocyclic ring or heterocyclic ring is optionally independently     substituted with one or more substituents independently selected     from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy,     NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, R⁶ and R⁷ are each independently selected from     a C₂-C₆ alkyl, C₂-C₆ haloalkyl, C₂-C₆ alkoxy, C₁-C₆ haloalkoxy, I,     CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl,     OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl),     OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,     CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl and     3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl, -   wherein R⁶ and R⁷ are each optionally substituted with one or more     substituents independently selected from hydroxy, halo, CN, oxo,     C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3-     to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered     heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆     alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3-     to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy,     and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy     that R⁶ or R⁷ is substituted with is optionally substituted with one     or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is     optionally fused to a five- to -seven-membered carbocyclic ring or     heterocyclic ring containing one or two heteroatoms independently     selected from oxygen, sulfur and nitrogen;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or one pair of R⁶ and R⁷ on adjacent atoms, taken together with the     atoms connecting them, independently form at least one C₄-C₈     carbocyclic ring or at least one 5- to 8-membered heterocyclic ring     containing 1 or 2 heteroatoms and/or heteroatomic groups     independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, wherein     the selected heteroatoms and/or heteroatomic groups are cumulative     with the nitrogen atoms present in ring B, and wherein the     carbocyclic ring or heterocyclic ring is optionally independently     substituted with one or more substituents independently selected     from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy,     NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, B is

In some embodiments, B is

In some embodiments, B is

In certain embodiments (when B is

B is

or B is

each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl,

wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl;

wherein R⁷ is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is optionally substituted with one to two C₁-C₆ alkoxy;

or R⁶ and R⁷, taken together with the atoms connecting them, independently form C₄-C₇ carbocyclic ring or at least one 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, B is

In certain of these embodiments, each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl,

wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl;

wherein R⁷ is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is optionally substituted with one to two C₁-C₆ alkoxy.

In certain of these embodiments, the other R⁶ is C₁-C₆ alkyl. For example, each R⁶ is isopropyl (i.e., the substituted ring B is

-   In certain other embodiments (when the substituted ring B is

one R⁶ is C₁-C₆ alkyl; and the other R⁶ is C₆-C₁₀ aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from: hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl.

In certain of these embodiments, one R⁶ is C₁-C₆ alkyl; and the other R⁶ is C₆-C₁₀ aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C₁-C₆ alkyl, and C₁-C₆ alkoxy. For example, R⁶ is 5-6 (e.g., 6) membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, or thiazolyl) optionally substituted with a substituent selected from hydroxyl, halo, CN, C₁-C₆ alkyl, and C₁-C₆ alkoxy.

As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:

(e.g., R⁷ is halo (e.g., fluoro)).

In some embodiments, B is

In certain of these embodiments, one R⁶ is C₁-C₆ alkyl; and the other R⁶ is C₆-C₁₀ aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from: hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl.

In certain of these embodiments, one R⁶ is C₁-C₆ alkyl; and the other R⁶ is C₆-C₁₀ aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C₁-C₆ alkyl, and C₁-C₆ alkoxy. For example, R⁶ is 5-6 (e.g., 6) membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, or thiazolyl) optionally substituted with a substituent selected from hydroxyl, halo, CN, C₁-C₆ alkyl, and C₁-C₆ alkoxy.

In certain of the foregoing embodiments, each R⁷ is independently halo or cyano,

As a non-limiting example of the foregoing embodiments, substituted ring B is:

In some embodiments, B is

In some embodiments, B is

In certain embodiments (when B is

or B is

each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl,

wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl;

wherein each R⁷ is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is optionally substituted with one to two C₁-C₆ alkoxy;

or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₇ carbocyclic ring or at least one 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In certain embodiments (when B is

or B is

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and each pair of one R⁶ and one R⁷ taken together with the atoms connecting them independently form a C₄-C₇ carbocyclic ring or a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein each carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In certain of the foregoing embodiments, one pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₅ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In certain of these embodiments (when one pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₅ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹), the other pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₅ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

As non-limiting examples of the foregoing embodiments (when B is

the substituted ring B is:

As a non-limiting example of the foregoing embodiments (when B is

the substituted ring B is:

In certain of these embodiments (when o=2 and p=2 (e.g., B is

or B is

and one pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₅ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹),

the other pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₄ or C₆-7 (e.g., C₄) carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

As a non-limiting example, the substituted ring B is:

In certain of these embodiments (when o=2 and p=2 (e.g., B is

or B is

one pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₄ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In certain of these embodiments, the other pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₄ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments (when the substituted ring B is

and each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl,

wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl;

wherein each R⁷ is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is optionally substituted with one to two C₁-C₆ alkoxy;

or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₇ carbocyclic ring or at least one 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, ═NR¹⁰ COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹),

one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form one C₄-C₇ carbocyclic ring or one 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; and each of the remaining R⁶ and R⁷ is independently selected from C₁-C₆ alkyl and C₃-C₇ cycloalkyl.

In certain of these embodiments, one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form one C₄-C₇ (e.g., C₅) carbocyclic ring; and each of the remaining R⁶ and R⁷ is independently selected from C₁-C₆ alkyl and C₃-C₇ cycloalkyl.

As a non-limiting example of the foregoing embodiments, the substituted ring B is

As a non-limiting example, the substituted ring B is:

In some embodiments, B is

In certain of these embodiments, each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl,

wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl;

wherein each R⁷ is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is optionally substituted with one to two C₁-C₆ alkoxy;

or R⁶ and R⁷, taken together with the atoms connecting them, independently form C₄-C₇ carbocyclic ring or at least one 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, B is

In certain of these embodiments, each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl,

wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl;

wherein each R⁷ is independently selected from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is optionally substituted with one to two C₁-C₆ alkoxy;

or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₇ carbocyclic ring or at least one 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In certain of the foregoing embodiments, two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and each pair of one R⁶ and one R⁷ taken together with the atoms connecting them independently form a C₄-C₇ carbocyclic ring or a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein each carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In certain of these embodiments, one pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₅ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In certain of the foregoing embodiments, the other pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₅ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

As a non-limiting example of the foregoing embodiments, the substituted ring B is:

For example, R⁷ is selected from each R⁷ is independently selected from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, and CN.

In some embodiments, the substituted ring B is selected from:

In certain of the foregoing embodiments, each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-Cm aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl, CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl,

wherein each of the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, 4- to 6-membered heterocycloalkyl, C₆-Cm aryl, and 5- to 10-membered heteroaryl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl;

wherein R⁷ is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein each of the C₁-C₆ alkyl is optionally substituted with C₁-C₆ alkoxy;

or R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form C₄-C₇ carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In certain of these embodiments, the R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form C₄-C₇ (e.g., C₄ or C₅) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹. For example, the R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form C₄-C₇ (e.g., C₅) carbocyclic ring. For example, the substituted ring B is

In certain embodiments (when the substituted ring B is selected from:

and the R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form C₄-C₇ (e.g., C₄ or C₅) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹):

the remaining R⁶ is C₆-C₁₀ aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl.

In certain of these embodiments, the remaining R⁶ is C₆-C₁₀ aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C₁-C₆ alkyl, and C₁-C₆ alkoxy. For example, R⁶ is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C₁-C₆ alkyl, and C₁-C₆ alkoxy.

As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:

(e.g., R⁷ is halo (e.g., fluoro)).

In some embodiments, the substituted ring B is selected from:

In certain of the foregoing embodiments, each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl, CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl,

wherein each of the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, and 5- to 10-membered heteroaryl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl;

wherein R⁷ is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is optionally substituted with one to two C₁-C₆ alkoxy;

or one pair R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form C₄-C₇ carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In certain of these embodiments, one pair R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form C₄-C₇ (e.g., C₄ or C₅) carbocyclic ring or 5-to-7-membered membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹. For example, the R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form C₄-C₇ (e.g., C₅) carbocyclic ring. For example, the substituted ring B is:

In certain embodiments (when the substituted ring B is selected from:

and one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form C₄-C₇ (e.g., C₄ or C₅) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹):

the remaining R⁶ is C₆-C₁₀ aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl.

In certain of these embodiments, the remaining R⁶ is C₆-C₁₀ aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C₁-C₆ alkyl, and C₁-C₆ alkoxy. For example, R⁶ is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C₁-C₆ alkyl, and C₁-C₆ alkoxy.

As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:

(e.g., R⁷ is halo (e.g., fluoro)).

The Group R³

-   In some embodiments, R³ is hydrogen or C₁-C₆ alkyl. -   In certain of these embodiments, R³ is hydrogen or methyl. -   In some embodiments, R³ is other than cyano. -   In some embodiments, R³ is selected from hydrogen, C₁-C₆ alkyl, and

wherein the C₁-C₂ alkylene group is optionally substituted with oxo.

-   In some embodiments, R³ is hydrogen. -   In some embodiments, R³ is cyano. -   In some embodiments, R³ is hydroxy. -   In some embodiments, R³ is C₁-C₆ alkoxy. In some embodiments, R³ is     C₁-C₆ alkyl. -   In some embodiments, R³ is methyl. -   In some embodiments, R³ is

wherein the C₁-C₂ alkylene group is optionally substituted with oxo.

-   In some embodiments, R³ is —CH₂R¹⁴. -   In some embodiments, R³ is —C(O)R¹⁴. -   In some embodiments, R³ is —CH₂CH₂R¹⁴. -   In some embodiments, R³ is —CHR¹⁴CH₃. -   In some embodiments, R³ is —CH₂C(O)R¹⁴. -   In some embodiments, R³ is —C(O)CH₂R¹⁴. -   In some embodiments, R³ is CO₂C₁-C₆ alkyl.

The Group R¹⁴

-   In some embodiments, R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered     monocyclic or bicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic     aryl, wherein each C₁-C₆ alkyl, aryl or heteroaryl is optionally     independently substituted with 1 or 2 R⁶. -   In some embodiments, R¹⁴ is hydrogen or C₁-C₆ alkyl. -   In some embodiments, R¹⁴ is hydrogen, 5- to 10-membered monocyclic     or bicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl,     wherein each C₁-C₆ alkyl, aryl or heteroaryl is optionally     independently substituted with 1 or 2 R⁶. -   In some embodiments, R¹⁴ is hydrogen. -   In some embodiments, R¹⁴ is C₁-C₆ alkyl. -   In some embodiments, R¹⁴ is methyl. -   In some embodiments, R¹⁴ is 5- to 10-membered monocyclic or bicyclic     heteroaryl optionally independently substituted with 1 or 2 R⁶. -   In some embodiments, R¹⁴ is C₆-C₁₀ monocyclic or bicyclic aryl     optionally independently substituted with 1 or 2 R⁶.     The moiety S(═O)(NHR³)═N— -   In some embodiments, the sulfur in the moiety S(═O)(NHR³)═N— has (S)     stereochemistry. -   In some embodiments, the sulfur in the moiety S(═O)(NHR³)═N— has (R)     stereochemistry.

The Group R¹⁰

-   In some embodiments, R¹⁰ is C₁-C₆ alkyl. -   In some embodiments, R¹⁰ is methyl. -   In some embodiments, R¹⁰ is ethyl.     The Groups R⁸ and R⁹ -   In some embodiments, each of R⁸ and R⁹ at each occurrence is     independently selected from hydrogen, C₁-C₆ alkyl, (C═NR¹³)NR¹¹R¹²,     S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein     the C₁-C₆ alkyl is optionally substituted with one or more hydroxy,     halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇     cycloalkyl or 3- to 7-membered heterocycloalkyl; or R⁸ and R⁹ taken     together with the nitrogen they are attached to form a 3- to     7-membered ring optionally containing one or more heteroatoms in     addition to the nitrogen they are attached to. -   In some embodiments, each of R⁸ and R⁹ at each occurrence is     independently selected from hydrogen, C₁-C₆ alkyl, (C═NR¹³)NR¹¹R¹²,     S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein     the C₁-C₆ alkyl is optionally substituted with one or more hydroxy,     halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇     cycloalkyl or 3- to 7-membered heterocycloalkyl; or R⁸ and R⁹ taken     together with the nitrogen they are attached to form a 3- to     7-membered ring optionally containing one or more heteroatoms in     addition to the nitrogen they are attached to. -   In some embodiments, each of R⁸ and R⁹ at each occurrence is     hydrogen, -   In some embodiments, each R⁸ at each occurrence is hydrogen and each     R⁹ at each occurrence is C₁-C₆ alkyl. -   In some embodiments, each R⁸ at each occurrence is hydrogen and each     R⁹ at each occurrence is methyl. -   In some embodiments, each R⁸ at each occurrence is hydrogen and each     R⁹ at each occurrence is ethyl. -   In some embodiments, each of R⁸ and R⁹ at each occurrence is methyl. -   In some embodiments, each of R⁸ and R⁹ at each occurrence is ethyl. -   In some embodiments, R⁸ and R⁹ taken together with the nitrogen they     are attached to form a 3-membered ring. -   In some embodiments, R⁸ and R⁹ taken together with the nitrogen they     are attached to form a 4-membered ring. -   In some embodiments, R⁸ and R⁹ taken together with the nitrogen they     are attached to form a 5-membered ring. -   In some embodiments, R⁸ and R⁹ taken together with the nitrogen they     are attached to form a 6-membered ring optionally containing one or     more oxygen atoms in addition to the nitrogen they are attached to. -   In some embodiments, R⁸ and R⁹ taken together with the nitrogen they     are attached to form a 6-membered ring optionally containing one or     more nitrogen atoms in addition to the nitrogen they are attached     to. -   In some embodiments, R⁸ and R⁹ taken together with the nitrogen they     are attached to form a 7-membered ring. -   In some embodiments, one of R⁸ and R⁹ is C(O)R¹³; R¹³ is     —(Z¹—Z²)_(a1)—Z³; and a1 is 0. -   In certain of these embodiments, the other one of R⁸ and R⁹ is     hydrogen.

As a non-limiting example of the foregoing embodiments, NR⁸R⁹ is selected from the group consisting of: NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl.

-   In some embodiments, one of R⁸ and R⁹ is C(O)R¹³; R¹³ is C₁-C₆     alkyl. -   In certain embodiments, NR⁸R⁹ is selected from the group consisting     of: NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀     aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered     heterocycloalkyl), NHCOC₂-C₆ alkynyl, and NHCOOC₁-C₆ alkyl.

The Group R¹³

-   In some embodiments, R¹³ is C₁-C₆ alkyl. -   In some embodiments, R¹³ is methyl. -   In some embodiments, R¹³ is ethyl. -   In some embodiments, R¹³ is —(Z¹—Z²)_(a1)—Z³. -   In certain of these embodiments, a1 is 0. In certain embodiments, Z³     is C₆-C₁₀ aryl or 5- to 10-membered heteroaryl. -   In some embodiments, R¹³ is C₆-C₁₀ aryl. -   In some embodiments, R¹³ is phenyl. -   In some embodiments, R¹³ is 5- to 10-membered heteroaryl.     The Groups R¹¹ and R¹² -   In some embodiments, each of R¹¹ and R¹² at each occurrence is     independently selected from hydrogen and C₁-C₆ alkyl. -   In some embodiments, each of R¹¹ and R¹² at each occurrence is     hydrogen, -   In some embodiments, each R¹¹ at each occurrence is hydrogen and     each R¹² at each occurrence is C₁-C₆ alkyl. -   In some embodiments, each R¹¹ at each occurrence is hydrogen and     each R¹² at each occurrence is methyl. -   In some embodiments, each R¹¹ at each occurrence is hydrogen and     each R¹² at each occurrence is ethyl. -   In some embodiments, each of R¹¹ and R¹² at each occurrence is     methyl. -   In some embodiments, each of R¹¹ and R¹² at each occurrence is     ethyl.

The Group R¹⁵

-   In some embodiments, R¹⁵ is —(Z⁴—Z⁵)_(a2)—Z⁶. -   In certain embodiments, a2 is 1-5. -   In certain embodiments, the Z⁴ group directly attached to R¹ or R²     is —O—. -   In certain embodiments, each Z⁴ is independently —O— or —NH—,     provided that the Z⁴ group directly attached to R¹ or R² is —O—. -   In certain embodiments, each Z⁴ is —O—. -   In certain embodiments, each Z⁵ is independently C₂-C₆ alkylene     optionally substituted with one or more substituents independently     selected from oxo, halo, and hydroxyl. In certain these embodiments,     each Z⁵ is independently C₂-C₄ (e.g., C₂-C₃ (e.g., C₂ or C₃))     alkylene. -   In certain embodiments, Z⁶ is OH. -   In certain embodiments, Z⁶ is NHC(O)(C₁-C₆ alkoxy). -   In certain embodiments, Z⁶ is C₆-C₁₀ aryl. -   In certain embodiments, Z⁶ is C₁-C₆ alkoxy. -   In certain embodiments of R¹⁵, a2=1; and Z⁴ is 0. In certain of     these embodiments, Z⁵ is C₂-C₄ (e.g., C₂-C₃ (e.g., C₂ or C₃))     alkylene. In certain of the foregoing embodiments, Z⁶ is selected     from OH, NHC(O)(C₁-C₆ alkoxy), and C₁-C₆ alkoxy.

As non-limiting examples, R¹⁵ is selected from:

-   In certain embodiments of R¹⁵, a2=1; and each Z⁴ is 0. In certain of     these embodiments, Z⁵ is C₂-C₄ (e.g., C₂-C₃ (e.g., C₂ or C₃))     alkylene. In certain of the foregoing embodiments, Z⁶ is selected     from OH, NHC(O)(C₁-C₆ alkoxy), and C₁-C₆ alkoxy. In certain other of     the foregoing embodiments, Z⁶ is C₆-C₁₀ aryl (e.g., R¹⁵ is

-   In certain embodiments of R¹⁵, a2≥2 (e.g., a2 is 3 or 4); each Z⁴ is     0; and each Z⁵ is ethylene. In certain of these embodiments Z⁶ is     OH. In certain other embodiments, Z⁶ is NHC(O)(C₁-C₆ alkoxy) (e.g.,     Boc). As a non-limiting example, R¹⁵ is:

-   In some embodiments of the compound of formula AA, -   the substituted ring A is

and R¹ is selected from:

-   C₁-C₆ alkyl optionally substituted with one or more hydroxy; C₃-C₇     cycloalkyl optionally substituted with one or more hydroxy; 3- to     7-membered heterocycloalkyl optionally substituted with one or more     hydroxy; C₁-C₆ alkyl substituted with one or more oxo; C₃-C₇     cycloalkyl substituted with one or more oxo; C₁-C₆ alkyl substituted     with one or more C₁-C₆ alkoxy; C₃-C₇ cycloalkyl substituted with one     or more C₁-C₆ alkoxy; C₁-C₆ haloalkyl; C₁-C₆ alkoxy; C₁-C₆     haloalkoxy; halo; CN; NO₂; COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to     10-membered heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl;     OCOC₁-C₆ alkyl; OCOC₆-C₁₀ aryl; OCO(5- to 10-membered heteroaryl);     OCO(3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to     10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂;     CONR⁸R⁹; SF₅; and S(O₂)C₁-C₆ alkyl. -   In some embodiments of the compound of formula AA, -   the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;         2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;         2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;         1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;         1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;         COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;         1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;         pyrazolyl; and S(O₂)CH₃.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;         C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy; 3- to 7-membered heterocycloalkyl optionally         substituted with one or more hydroxy; C₁-C₆ alkyl substituted         with one or more oxo; C₃-C₇ cycloalkyl substituted with one or         more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;         C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;         C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered         heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆         haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;         COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl);         CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀         aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered         heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl;         NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; and         S(O₂)C₁-C₆ alkyl.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;         2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;         2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;         1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;         1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;         COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;         1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;         pyrazolyl; and S(O₂)CH₃.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;         C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy; 3- to 7-membered heterocycloalkyl optionally         substituted with one or more hydroxy; C₁-C₆ alkyl substituted         with one or more oxo; C₃-C₇ cycloalkyl substituted with one or         more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;         C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;         C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered         heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆         haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;         COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl);         CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀         aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered         heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl;         NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; and         S(O₂)C₁-C₆ alkyl.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;         2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;         2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;         1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;         1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;         COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;         1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;         pyrazolyl; and S(O₂)CH₃.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;         C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy; 3- to 7-membered heterocycloalkyl optionally         substituted with one or more hydroxy; C₁-C₆ alkyl substituted         with one or more oxo; C₃-C₇ cycloalkyl substituted with one or         more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;         C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;         C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered         heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆         haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;         COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl);         CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀         aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered         heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl;         NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; and         S(O₂)C₁-C₆ alkyl.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;         2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;         2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;         1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;         1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;         COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;         1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;         pyrazolyl; and S(O₂)CH₃.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;         C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy; 3- to 7-membered heterocycloalkyl optionally         substituted with one or more hydroxy; C₁-C₆ alkyl substituted         with one or more oxo; C₃-C₇ cycloalkyl substituted with one or         more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;         C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;         C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered         heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆         haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;         COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl);         CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀         aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered         heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl;         NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; and         S(O₂)C₁-C₆ alkyl.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;         2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;         2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;         1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;         1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;         COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;         1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;         pyrazolyl; and S(O₂)CH₃.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;         C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy; 3- to 7-membered heterocycloalkyl optionally         substituted with one or more hydroxy; C₁-C₆ alkyl substituted         with one or more oxo; C₃-C₇ cycloalkyl substituted with one or         more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;         C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;         C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered         heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆         haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;         COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl);         CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀         aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered         heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl;         NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; and         S(O₂)C₁-C₆ alkyl.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;         2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;         2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;         1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;         1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;         COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;         1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;         pyrazolyl; and S(O₂)CH₃.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;         C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy; 3- to 7-membered heterocycloalkyl optionally         substituted with one or more hydroxy; C₁-C₆ alkyl substituted         with one or more oxo; C₃-C₇ cycloalkyl substituted with one or         more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;         C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;         C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered         heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆         haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;         COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl);         CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀         aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered         heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl;         NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; and         S(O₂)C₁-C₆ alkyl.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;         2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;         2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;         1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;         1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;         COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;         1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;         pyrazolyl; and S(O₂)CH₃.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;         C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy; 3- to 7-membered heterocycloalkyl optionally         substituted with one or more hydroxy; C₁-C₆ alkyl substituted         with one or more oxo; C₃-C₇ cycloalkyl substituted with one or         more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;         C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;         C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered         heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆         haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;         COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl);         CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀         aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered         heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl;         NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; and         S(O₂)C₁-C₆ alkyl.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;         2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;         2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;         1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;         1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;         COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;         1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;         pyrazolyl; and S(O₂)CH₃.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;         C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy; 3- to 7-membered heterocycloalkyl optionally         substituted with one or more hydroxy; C₁-C₆ alkyl substituted         with one or more oxo; C₃-C₇ cycloalkyl substituted with one or         more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;         C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;         C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered         heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆         haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;         COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl);         CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀         aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered         heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl;         NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; and         S(O₂)C₁-C₆ alkyl.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;         2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;         2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;         1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;         1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;         COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;         1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;         pyrazolyl; and S(O₂)CH₃.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;         C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy; 3- to 7-membered heterocycloalkyl optionally         substituted with one or more hydroxy; C₁-C₆ alkyl substituted         with one or more oxo; C₃-C₇ cycloalkyl substituted with one or         more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;         C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;         C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered         heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆         haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;         COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl);         CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀         aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered         heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl;         NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; and         S(O₂)C₁-C₆ alkyl.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;         2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;         2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;         1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;         1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;         COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;         1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;         pyrazolyl; and S(O₂)CH₃.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;         C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy; 3- to 7-membered heterocycloalkyl optionally         substituted with one or more hydroxy; C₁-C₆ alkyl substituted         with one or more oxo; C₃-C₇ cycloalkyl substituted with one or         more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;         C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;         C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered         heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆         haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;         COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl);         CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀         aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered         heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl;         NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; and         S(O₂)C₁-C₆ alkyl.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;         2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;         2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;         1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;         1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;         COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;         1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;         pyrazolyl; and S(O₂)CH₃.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;         C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy; 3- to 7-membered heterocycloalkyl optionally         substituted with one or more hydroxy; C₁-C₆ alkyl substituted         with one or more oxo; C₃-C₇ cycloalkyl substituted with one or         more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;         C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;         C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered         heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆         haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;         COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl);         CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀         aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered         heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl;         NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; and         S(O₂)C₁-C₆ alkyl.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;         2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;         2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;         1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;         1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;         COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;         1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;         pyrazolyl; and S(O₂)CH₃.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;         C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy; 3- to 7-membered heterocycloalkyl optionally         substituted with one or more hydroxy; C₁-C₆ alkyl substituted         with one or more oxo; C₃-C₇ cycloalkyl substituted with one or         more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;         C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;         C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered         heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆         haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;         COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl);         CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀         aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered         heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl;         NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; and         S(O₂)C₁-C₆ alkyl.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;         2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;         2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;         1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;         1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;         COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;         1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;         pyrazolyl; and S(O₂)CH₃.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;         C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy; 3- to 7-membered heterocycloalkyl optionally         substituted with one or more hydroxy; C₁-C₆ alkyl substituted         with one or more oxo; C₃-C₇ cycloalkyl substituted with one or         more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;         C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;         C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered         heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆         haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;         COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl);         CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀         aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered         heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl;         NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; and         S(O₂)C₁-C₆ alkyl.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;         2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;         2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;         1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;         1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;         COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;         1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;         pyrazolyl; and S(O₂)CH₃.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;         C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy; 3- to 7-membered heterocycloalkyl optionally         substituted with one or more hydroxy; C₁-C₆ alkyl substituted         with one or more oxo; C₃-C₇ cycloalkyl substituted with one or         more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;         C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;         C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered         heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆         haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;         COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl);         CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀         aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered         heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl;         NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; and         S(O₂)C₁-C₆ alkyl.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;         2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;         2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;         1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;         1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;         COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;         1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;         pyrazolyl; and S(O₂)CH₃.

-   the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;         C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy; 3- to 7-membered heterocycloalkyl optionally         substituted with one or more hydroxy; C₁-C₆ alkyl substituted         with one or more oxo; C₃-C₇ cycloalkyl substituted with one or         more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;         C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;         C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered         heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆         haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;         COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl);         CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀         aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered         heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl;         NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; and         S(O₂)C₁-C₆ alkyl.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;         2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;         2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;         1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;         1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;         COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;         1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;         pyrazolyl; and S(O₂)CH₃.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;         C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy; 3- to 7-membered heterocycloalkyl optionally         substituted with one or more hydroxy; C₁-C₆ alkyl substituted         with one or more oxo; C₃-C₇ cycloalkyl substituted with one or         more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;         C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;         C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered         heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆         haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;         COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO-5- to 10-membered heteroaryl;         CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀         aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered         heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl;         NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; and         S(O₂)C₁-C₆ alkyl.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;         2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;         2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;         1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;         1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;         COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;         1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;         pyrazolyl; and S(O₂)CH₃.

In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;         C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy; 3- to 7-membered heterocycloalkyl optionally         substituted with one or more hydroxy; C₁-C₆ alkyl substituted         with one or more oxo; C₃-C₇ cycloalkyl substituted with one or         more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;         C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;         C₁-C₆ alkyl substituted with one or more NR⁸R⁹; 3- to 7-membered         heterocycloalkyl substituted with one or more NR⁸R⁹; C₁-C₆         haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;         COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl);         CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀         aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered         heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl;         NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; and         S(O₂)C₁-C₆ alkyl.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;         2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;         2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;         1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;         1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;         COCH₂CH₃; 2-methoxy-2-propyl; (dimethylamino)methyl;         1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl;         pyrazolyl; and S(O₂)CH₃.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;         C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy; 3- to 7-membered heterocycloalkyl optionally         substituted with one or more hydroxy; C₁-C₆ alkyl substituted         with one or more oxo; C₃-C₇ cycloalkyl substituted with one or         more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;         C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;         C₁-C₆ haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;         COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl);         CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀         aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered         heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl;         NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; C₁-C₆ alkyl         substituted with one or more NR⁸R⁹; and S(O₂)C₁-C₆ alkyl.

-   the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;         2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;         2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;         1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;         1-hydroxy-1-cyclohexyl; morpholinyl; (dimethylamino)methyl;         1,3-dioxolan-2-yl; COCH₃; COCH₂CH₃; 2-methoxy-2-propyl; fluoro;         chloro; phenyl; pyridyl; pyrazolyl; and S(O₂)CH₃.

-   the substituted ring A is

and R¹ is selected from:

-   -   C₁-C₆ alkyl optionally substituted with one or more hydroxy;         C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy; 3- to 7-membered heterocycloalkyl optionally         substituted with one or more hydroxy; C₁-C₆ alkyl substituted         with one or more oxo; C₃-C₇ cycloalkyl substituted with one or         more oxo; C₁-C₆ alkyl substituted with one or more C₁-C₆ alkoxy;         C₃-C₇ cycloalkyl substituted with one or more C₁-C₆ alkoxy;         C₁-C₆ haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂;         COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl);         CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀         aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered         heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl;         NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; C₁-C₆ alkyl         substituted with one or more NR⁸R⁹; and S(O₂)C₁-C₆ alkyl.

-   the substituted ring A is

and R¹ is selected from:

-   -   1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl;         2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl;         2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl;         1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl;         1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH₃;         COCH₂CH₃; 2-methoxy-2-propyl; fluoro; chloro; phenyl; pyridyl;         pyrazolyl; (dimethylamino)methyl; and S(O₂)CH₃.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one         or more hydroxy;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₆-C₁₀ aryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is 5- to 10-membered heteroaryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is SF₅;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is S(O₂)C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is halo;     -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is halo;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R² is methyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is C₆-C₁₀ aryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is SF₅.     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is halo;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R¹ is C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is halo.

-   In some embodiments of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;     -   R¹ is hydroxymethyl and R² is methyl;     -   R¹ is 1-hydroxyethyl and R² is methyl;     -   R¹ is 2-hydroxyethyl and R² is methyl;     -   R¹ is 1-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;     -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;     -   R¹ is 2-hydroxy-2-propyl and R² is chloro;     -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;     -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;     -   R¹ is morpholinyl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;     -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;     -   R¹ is COCH₃, and R² is methyl;     -   R¹ is 2-methoxy-2-propyl, and R² is methyl;     -   R² is (dimethylamino)methyl, and R¹ is methyl.     -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;     -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;     -   R² is hydroxymethyl and R¹ is methyl;     -   R² is 1-hydroxyethyl and R¹ is methyl;     -   R² is 2-hydroxyethyl and R¹ is methyl;     -   R² is 1-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)CH₃;     -   R² is 2-hydroxy-2-propyl and R¹ is chloro;     -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;     -   R² is morpholinyl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;     -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl;     -   R² is COCH₃, and R¹ is methyl; or     -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one         or more hydroxy;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₆-C₁₀ aryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is 5- to 10-membered heteroaryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is SF₅;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is S(O₂)C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is halo;     -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is halo;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R² is methyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is C₆-C₁₀ aryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is SF₅.     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is halo;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl;         -   or     -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R¹ is C₁-C₆ alkyl.     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is C₁-C₆ alkyl;         -   or     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is halo.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;     -   R¹ is hydroxymethyl and R² is methyl;     -   R¹ is 1-hydroxyethyl and R² is methyl;     -   R¹ is 2-hydroxyethyl and R² is methyl;     -   R¹ is 1-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;     -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;     -   R¹ is 2-hydroxy-2-propyl and R² is chloro;     -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;     -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;     -   R¹ is morpholinyl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;     -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;     -   R¹ is COCH₃, and R² is methyl;     -   R¹ is 2-methoxy-2-propyl, and R² is methyl;     -   R¹ is (dimethylamino)methyl, and R² is methyl.     -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;     -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;     -   R² is hydroxymethyl and R¹ is methyl;     -   R² is 1-hydroxyethyl and R¹ is methyl;     -   R² is 2-hydroxyethyl and R¹ is methyl;     -   R² is 1-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)CH₃;     -   R² is 2-hydroxy-2-propyl and R¹ is chloro;     -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;     -   R² is morpholinyl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;     -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl;     -   R² is (dimethylamino)methyl, and R¹ is methyl;     -   R² is COCH₃, and R¹ is methyl; or     -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one         or more hydroxy;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₆-C₁₀ aryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is 5- to 10-membered heteroaryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is SF₅;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is S(O₂)C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is halo;     -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is halo;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R² is methyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is C₆-C₁₀ aryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is SF₅.     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is halo;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl; or     -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R¹ is C₁-C₆ alkyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;     -   R¹ is hydroxymethyl and R² is methyl;     -   R¹ is 1-hydroxyethyl and R² is methyl;     -   R¹ is 2-hydroxyethyl and R² is methyl;     -   R¹ is 1-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;     -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;     -   R¹ is 2-hydroxy-2-propyl and R² is chloro;     -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;     -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;     -   R¹ is morpholinyl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;     -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;     -   R¹ is COCH₃, and R² is methyl;     -   R¹ is 2-methoxy-2-propyl, and R² is methyl;     -   R¹ is (dimethylamino)methyl, and R² is methyl;     -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;     -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;     -   R² is hydroxymethyl and R¹ is methyl;     -   R² is 1-hydroxyethyl and R¹ is methyl;     -   R² is 2-hydroxyethyl and R¹ is methyl;     -   R² is 1-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)CH₃;     -   R² is 2-hydroxy-2-propyl and R¹ is chloro;     -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;     -   R² is morpholinyl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;     -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl;     -   R² is (dimethylamino)methyl, and R¹ is methyl;     -   R² is COCH₃, and R¹ is methyl; or     -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one         or more hydroxy;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₆-C₁₀ aryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is 5- to 10-membered heteroaryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is SF₅;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is S(O₂)C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is halo;     -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is halo;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R² is methyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is C₆-C₁₀ aryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is SF₅.     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is halo;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl; or     -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R¹ is C₁-C₆ alkyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;     -   R¹ is hydroxymethyl and R² is methyl;     -   R¹ is 1-hydroxyethyl and R² is methyl;     -   R¹ is 2-hydroxyethyl and R² is methyl;     -   R¹ is 1-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;     -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;     -   R¹ is 2-hydroxy-2-propyl and R² is chloro;     -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;     -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;     -   R¹ is morpholinyl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;     -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;     -   R¹ is COCH₃, and R² is methyl;     -   R¹ is 2-methoxy-2-propyl, and R² is methyl;     -   R¹ is (dimethylamino)methyl, and R² is methyl.     -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;     -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;     -   R² is hydroxymethyl and R¹ is methyl;     -   R² is 1-hydroxyethyl and R¹ is methyl;     -   R² is 2-hydroxyethyl and R¹ is methyl;     -   R² is 1-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)CH₃;     -   R² is 2-hydroxy-2-propyl and R¹ is chloro;     -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;     -   R² is morpholinyl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;     -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl;     -   R² is (dimethylamino)methyl, and R¹ is methyl;     -   R² is COCH₃, and R¹ is methyl; or     -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one         or more hydroxy;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₆-C₁₀ aryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is 5- to 10-membered heteroaryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is SF₅;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is S(O₂)C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is halo;     -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is halo;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R² is methyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is C₆-C₁₀ aryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is SF₅.     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is halo;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl; or     -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R¹ is C₁-C₆ alkyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;     -   R¹ is hydroxymethyl and R² is methyl;     -   R¹ is 1-hydroxyethyl and R² is methyl;     -   R¹ is 2-hydroxyethyl and R² is methyl;     -   R¹ is 1-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;     -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;     -   R¹ is 2-hydroxy-2-propyl and R² is chloro;     -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;     -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;     -   R¹ is morpholinyl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;     -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;     -   R¹ is COCH₃, and R² is methyl;     -   R¹ is 2-methoxy-2-propyl, and R² is methyl;     -   R¹ is (dimethylamino)methyl, and R² is methyl.     -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;     -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;     -   R² is hydroxymethyl and R¹ is methyl;     -   R² is 1-hydroxyethyl and R¹ is methyl;     -   R² is 2-hydroxyethyl and R¹ is methyl;     -   R² is 1-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)CH₃;     -   R² is 2-hydroxy-2-propyl and R¹ is chloro;     -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;     -   R² is morpholinyl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;     -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl;     -   R² is (dimethylamino)methyl, and R¹ is methyl;     -   R² is COCH₃, and R¹ is methyl; or     -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one         or more hydroxy;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₆-C₁₀ aryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is 5- to 10-membered heteroaryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is SF₅;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is S(O₂)C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is halo;     -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is halo;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R² is methyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is C₆-C₁₀ aryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is SF₅.     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is halo;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl; or     -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R¹ is C₁-C₆ alkyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;     -   R¹ is hydroxymethyl and R² is methyl;     -   R¹ is 1-hydroxyethyl and R² is methyl;     -   R¹ is 2-hydroxyethyl and R² is methyl;     -   R¹ is 1-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;     -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;     -   R¹ is 2-hydroxy-2-propyl and R² is chloro;     -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;     -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;     -   R¹ is morpholinyl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;     -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;     -   R¹ is COCH₃, and R² is methyl;     -   R¹ is 2-methoxy-2-propyl, and R² is methyl;     -   R¹ is (dimethylamino)methyl, and R² is methyl.     -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;     -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;     -   R² is hydroxymethyl and R¹ is methyl;     -   R² is 1-hydroxyethyl and R¹ is methyl;     -   R² is 2-hydroxyethyl and R¹ is methyl;     -   R² is 1-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)CH₃;     -   R² is 2-hydroxy-2-propyl and R¹ is chloro;     -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;     -   R² is morpholinyl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;     -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl;     -   R² is (dimethylamino)methyl, and R¹ is methyl;     -   R² is COCH₃, and R¹ is methyl; or     -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one         or more hydroxy;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₆-C₁₀ aryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is 5- to 10-membered heteroaryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is SF₅;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is S(O₂)C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is halo;     -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is halo;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R² is methyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is C₆-C₁₀ aryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is SF₅.     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is halo;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl; or     -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R¹ is C₁-C₆ alkyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;     -   R¹ is hydroxymethyl and R² is methyl;     -   R¹ is 1-hydroxyethyl and R² is methyl;     -   R¹ is 2-hydroxyethyl and R² is methyl;     -   R¹ is 1-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;     -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;     -   R¹ is 2-hydroxy-2-propyl and R² is chloro;     -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;     -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;     -   R¹ is morpholinyl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;     -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;     -   R¹ is COCH₃, and R² is methyl;     -   R¹ is 2-methoxy-2-propyl, and R² is methyl;     -   R¹ is (dimethylamino)methyl, and R² is methyl.     -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;     -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;     -   R² is hydroxymethyl and R¹ is methyl;     -   R² is 1-hydroxyethyl and R¹ is methyl;     -   R² is 2-hydroxyethyl and R¹ is methyl;     -   R² is 1-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)CH₃;     -   R² is 2-hydroxy-2-propyl and R¹ is chloro;     -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;     -   R² is morpholinyl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;     -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl;     -   R² is (dimethylamino)methyl, and R¹ is methyl;     -   R² is COCH₃, and R¹ is methyl; or     -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one         or more hydroxy;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₆-C₁₀ aryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is 5- to 10-membered heteroaryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is SF₅;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is S(O₂)C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is halo;     -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is halo;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R² is methyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is C₆-C₁₀ aryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is SF₅.     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is halo;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl; or     -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R¹ is C₁-C₆ alkyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;     -   R¹ is hydroxymethyl and R² is methyl;     -   R¹ is 1-hydroxyethyl and R² is methyl;     -   R¹ is 2-hydroxyethyl and R² is methyl;     -   R¹ is 1-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;     -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;     -   R¹ is 2-hydroxy-2-propyl and R² is chloro;     -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;     -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;     -   R¹ is morpholinyl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;     -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;     -   R¹ is COCH₃, and R² is methyl;     -   R¹ is 2-methoxy-2-propyl, and R² is methyl;     -   R¹ is (dimethylamino)methyl, and R² is methyl.     -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;     -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;     -   R² is hydroxymethyl and R¹ is methyl;     -   R² is 1-hydroxyethyl and R¹ is methyl;     -   R² is 2-hydroxyethyl and R¹ is methyl;     -   R² is 1-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)CH₃;     -   R² is 2-hydroxy-2-propyl and R¹ is chloro;     -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;     -   R² is morpholinyl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;     -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl;     -   R² is (dimethylamino)methyl, and R¹ is methyl;     -   R² is COCH₃, and R¹ is methyl; or     -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;     -   R¹ is hydroxymethyl and R² is methyl;     -   R¹ is 1-hydroxyethyl and R² is methyl;     -   R¹ is 2-hydroxyethyl and R² is methyl;     -   R¹ is 1-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;     -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;     -   R¹ is 2-hydroxy-2-propyl and R² is chloro;     -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;     -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;     -   R¹ is morpholinyl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;     -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;     -   R¹ is COCH₃, and R² is methyl;     -   R¹ is 2-methoxy-2-propyl, and R² is methyl;     -   R¹ is (dimethylamino)methyl, and R² is methyl.     -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;     -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;     -   R² is hydroxymethyl and R¹ is methyl;     -   R² is 1-hydroxyethyl and R¹ is methyl;     -   R² is 2-hydroxyethyl and R¹ is methyl;     -   R² is 1-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)CH₃;     -   R² is 2-hydroxy-2-propyl and R¹ is chloro;     -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;     -   R² is morpholinyl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;     -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl;     -   R² is (dimethylamino)methyl, and R¹ is methyl;     -   R² is COCH₃, and R¹ is methyl; or     -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one         or more hydroxy;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₆-C₁₀ aryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is 5- to 10-membered heteroaryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is SF₅;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is S(O₂)C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is halo;     -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is halo;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R² is methyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is C₆-C₁₀ aryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is SF₅.     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is halo;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl; or     -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R¹ is C₁-C₆ alkyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;     -   R¹ is hydroxymethyl and R² is methyl;     -   R¹ is 1-hydroxyethyl and R² is methyl;     -   R¹ is 2-hydroxyethyl and R² is methyl;     -   R¹ is 1-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;     -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;     -   R¹ is 2-hydroxy-2-propyl and R² is chloro;     -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;     -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;     -   R¹ is morpholinyl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;     -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;     -   R¹ is COCH₃, and R² is methyl;     -   R¹ is 2-methoxy-2-propyl, and R² is methyl;     -   R¹ is (dimethylamino)methyl, and R² is methyl.     -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;     -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;     -   R² is hydroxymethyl and R¹ is methyl;     -   R² is 1-hydroxyethyl and R¹ is methyl;     -   R² is 2-hydroxyethyl and R¹ is methyl;     -   R² is 1-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)CH₃;     -   R² is 2-hydroxy-2-propyl and R¹ is chloro;     -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;     -   R² is morpholinyl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;     -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl;     -   R² is (dimethylamino)methyl, and R¹ is methyl;     -   R² is COCH₃, and R¹ is methyl; or     -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one         or more hydroxy;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₆-C₁₀ aryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is 5- to 10-membered heteroaryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is SF₅;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is S(O₂)C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is halo;     -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is halo;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R² is methyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is C₆-C₁₀ aryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is SF₅.     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is halo;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl; or     -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R¹ is C₁-C₆ alkyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;     -   R¹ is hydroxymethyl and R² is methyl;     -   R¹ is 1-hydroxyethyl and R² is methyl;     -   R¹ is 2-hydroxyethyl and R² is methyl;     -   R¹ is 1-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;     -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;     -   R¹ is 2-hydroxy-2-propyl and R² is chloro;     -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;     -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;     -   R¹ is morpholinyl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;     -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;     -   R¹ is COCH₃, and R² is methyl;     -   R¹ is 2-methoxy-2-propyl, and R² is methyl;     -   R¹ is (dimethylamino)methyl, and R² is methyl.     -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;     -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;     -   R² is hydroxymethyl and R¹ is methyl;     -   R² is 1-hydroxyethyl and R¹ is methyl;     -   R² is 2-hydroxyethyl and R¹ is methyl;     -   R² is 1-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)CH₃;     -   R² is 2-hydroxy-2-propyl and R¹ is chloro;     -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;     -   R² is morpholinyl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;     -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl;     -   R² is (dimethylamino)methyl, and R¹ is methyl;     -   R² is COCH₃, and R¹ is methyl; or     -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one         or more hydroxy;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₆-C₁₀ aryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is 5- to 10-membered heteroaryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is SF₅;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is S(O₂)C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is halo;     -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is halo;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R² is methyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is C₆-C₁₀ aryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is SF₅.     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is halo;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl; or     -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R¹ is C₁-C₆ alkyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;     -   R¹ is hydroxymethyl and R² is methyl;     -   R¹ is 1-hydroxyethyl and R² is methyl;     -   R¹ is 2-hydroxyethyl and R² is methyl;     -   R¹ is 1-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;     -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;     -   R¹ is 2-hydroxy-2-propyl and R² is chloro;     -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;     -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;     -   R¹ is morpholinyl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;     -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;     -   R¹ is COCH₃, and R² is methyl;     -   R¹ is 2-methoxy-2-propyl, and R² is methyl;     -   R¹ is (dimethylamino)methyl, and R² is methyl.     -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;     -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;     -   R² is hydroxymethyl and R¹ is methyl;     -   R² is 1-hydroxyethyl and R¹ is methyl;     -   R² is 2-hydroxyethyl and R¹ is methyl;     -   R² is 1-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)CH₃;     -   R² is 2-hydroxy-2-propyl and R¹ is chloro;     -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;     -   R² is morpholinyl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;     -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl;     -   R² is (dimethylamino)methyl, and R¹ is methyl;     -   R² is COCH₃, and R¹ is methyl; or     -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one         or more hydroxy;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₆-C₁₀ aryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is 5- to 10-membered heteroaryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is SF₅;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is S(O₂)C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is halo;     -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is halo;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R² is methyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is C₆-C₁₀ aryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is SF₅.     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is halo;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl; or     -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R¹ is C₁-C₆ alkyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;     -   R¹ is hydroxymethyl and R² is methyl;     -   R¹ is 1-hydroxyethyl and R² is methyl;     -   R¹ is 2-hydroxyethyl and R² is methyl;     -   R¹ is 1-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;     -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;     -   R¹ is 2-hydroxy-2-propyl and R² is chloro;     -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;     -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;     -   R¹ is morpholinyl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;     -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;     -   R¹ is COCH₃, and R² is methyl;     -   R¹ is 2-methoxy-2-propyl, and R² is methyl;     -   R¹ is (dimethylamino)methyl, and R² is methyl.     -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;     -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;     -   R² is hydroxymethyl and R¹ is methyl;     -   R² is 1-hydroxyethyl and R¹ is methyl;     -   R² is 2-hydroxyethyl and R¹ is methyl;     -   R² is 1-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)CH₃;     -   R² is 2-hydroxy-2-propyl and R¹ is chloro;     -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;     -   R² is morpholinyl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;     -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;     -   R² is (dimethylamino)methyl, and R¹ is methyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl; or     -   R² is COCH₃, and R¹ is methyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one         or more hydroxy;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₆-C₁₀ aryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is 5- to 10-membered heteroaryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is SF₅;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is S(O₂)C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is halo;     -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is halo;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R² is methyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is C₆-C₁₀ aryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is SF₅.     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is halo;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl; or     -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R¹ is C₁-C₆ alkyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;     -   R¹ is hydroxymethyl and R² is methyl;     -   R¹ is 1-hydroxyethyl and R² is methyl;     -   R¹ is 2-hydroxyethyl and R² is methyl;     -   R¹ is 1-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;     -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;     -   R¹ is 2-hydroxy-2-propyl and R² is chloro;     -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;     -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;     -   R¹ is morpholinyl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;     -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;     -   R¹ is COCH₃, and R² is methyl;     -   R¹ is 2-methoxy-2-propyl, and R² is methyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is halo;     -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;     -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;     -   R² is hydroxymethyl and R¹ is methyl;     -   R² is 1-hydroxyethyl and R¹ is methyl;     -   R² is 2-hydroxyethyl and R¹ is methyl;     -   R² is 1-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)CH₃;     -   R² is 2-hydroxy-2-propyl and R¹ is chloro;     -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;     -   R² is morpholinyl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;     -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more Melt',         and R¹ is C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is halo;     -   R² is COCH₃, and R¹ is methyl; or     -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl optionally substituted with one         or more hydroxy;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is C₆-C₁₀ aryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is 5- to 10-membered heteroaryl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is SF₅;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is S(O₂)C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R² is halo;     -   R¹ is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is C₁-C₆ alkyl;     -   R¹ is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R² is halo;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R² is methyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is C₁-C₆ alkyl;     -   R¹ is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R² is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is C₆-C₁₀ aryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is SF₅.     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is halo;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 3- to 7-membered heterocycloalkyl optionally substituted         with one or more hydroxy, and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is C₁-C₆ alkyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more NR⁸R⁹,         and R¹ is halo;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl; or     -   R² is C₁-C₆ alkyl optionally substituted with one or more C₁-C₆         alkoxy, and R¹ is C₁-C₆ alkyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring A is

and R¹ and R² are one of the following combinations:

-   -   R¹ is 1-hydroxy-2-methylpropan-2-yl, and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is isopropyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 2-hydroxy-2-propyl;     -   R¹ is 2-hydroxy-2-propyl and R² is 1-hydroxyethyl;     -   R¹ is hydroxymethyl and R² is methyl;     -   R¹ is 1-hydroxyethyl and R² is methyl;     -   R¹ is 2-hydroxyethyl and R² is methyl;     -   R¹ is 1-hydroxy-2-propyl and R² is methyl;     -   R¹ is 2-hydroxy-2-propyl and R² is phenyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyridyl;     -   R¹ is 2-hydroxy-2-propyl and R² is pyrazolyl;     -   R¹ is 2-hydroxy-2-propyl, and R² is S(O₂)CH₃;     -   R¹ is 2-hydroxy-2-propyl and R² is chloro;     -   R¹ is 2-hydroxy-2-propyl and R² is fluoro;     -   R¹ is 1-hydroxy-1-cyclopropyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclobutyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclopentyl, and R² is methyl;     -   R¹ is 1-hydroxy-1-cyclohexyl, and R² is methyl;     -   R¹ is morpholinyl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is methyl;     -   R¹ is 1,3-dioxolan-2-yl, and R² is fluoro;     -   R¹ is 1,3-dioxolan-2-yl, and R² is chloro;     -   R¹ is COCH₃, and R² is methyl;     -   R¹ is 2-methoxy-2-propyl, and R² is methyl;     -   R¹ is (dimethylamino)methyl, and R² is methyl.     -   R² is 1-hydroxy-2-methylpropan-2-yl, and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is isopropyl;     -   R² is 2-hydroxy-2-propyl and R¹ is 1-hydroxyethyl;     -   R² is hydroxymethyl and R¹ is methyl;     -   R² is 1-hydroxyethyl and R¹ is methyl;     -   R² is 2-hydroxyethyl and R¹ is methyl;     -   R² is 1-hydroxy-2-propyl and R¹ is methyl;     -   R² is 2-hydroxy-2-propyl and R¹ is phenyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is 5- to 10-membered heteroaryl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyridyl;     -   R² is 2-hydroxy-2-propyl and R¹ is pyrazolyl;     -   R² is C₁-C₆ alkyl optionally substituted with one or more         hydroxy, and R¹ is S(O₂)CH₃;     -   R² is 2-hydroxy-2-propyl and R¹ is chloro;     -   R² is 2-hydroxy-2-propyl and R¹ is fluoro;     -   R² is C₃-C₇ cycloalkyl optionally substituted with one or more         hydroxy, and R¹ is C₁-C₆ alkyl;     -   R² is 1-hydroxy-1-cyclopropyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclobutyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclopentyl, and R¹ is methyl;     -   R² is 1-hydroxy-1-cyclohexyl, and R¹ is methyl;     -   R² is morpholinyl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is methyl;     -   R² is 1,3-dioxolan-2-yl, and R¹ is fluoro;     -   R² is 1,3-dioxolan-2-yl, and R¹ is chloro;     -   R² is C₁-C₆ alkyl optionally substituted with one or more oxo,         and R¹ is methyl;     -   R² is (dimethylamino)methyl, and R¹ is methyl;     -   R² is COCH₃, and R¹ is methyl; or     -   R² is 2-methoxy-2-propyl, and R¹ is methyl.

In some embodiments, the optionally substituted ring A is

R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂ (in addition to the nitrogen atom attached to R¹), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂ (in addition to the nitrogen atom attached to R²), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂ (in addition to the nitrogen attached to R²), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

one pair of R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

one pair of R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

one pair of R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂; and b) when one of the adjacent atoms is a nitrogen atom, then the heterocyclic ring includes from 0-2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂ (in addition to the aforementioned nitrogen atom attached to R¹), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

one pair of R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂ (in addition to the nitrogen atom attached to R¹), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

one pair of R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂; and b) when one of the adjacent atoms is a nitrogen atom, then the heterocyclic ring includes from 0-2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂ (in addition to the aforementioned nitrogen atom attached to R²), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

one pair of R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR¹³, S, S(O), and S(O)₂ (in addition to the nitrogen atom(s) attached to R²), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

-   In some embodiments of the compound of formula AA, -   the substituted ring B is

and R⁶ is selected from:

C₁-C₆ alkyl, C₁-C₆ alkyl substituted with one or more halo, C₁-C₆ alkoxy, C₁-C₆ alkoxy substituted with one or more halo, C₃-C₇ cycloalkyl, halo, and cyano.

-   In some embodiments of the compound of formula AA, -   the substituted ring B is

and R⁶ is selected from:

isopropyl, ethyl, methyl, trifluoromethyl, trifluoromethoxy, cyclopropyl, halo, chloro, and fluoro.

-   In some embodiments of the compound of formula AA, -   the substituted ring B is

and R⁶ is selected from:

C₁-C₆ alkyl, C₁-C₆ alkyl substituted with one or more halo, C₁-C₆ alkoxy, C₁-C₆ alkoxy substituted with one or more halo, C₃-C₇ cycloalkyl, halo, and cyano.

-   In some embodiments of the compound of formula AA, -   the substituted ring B is

and R⁶ is selected from:

isopropyl, ethyl, methyl, trifluoromethyl, trifluoromethoxy, cyclopropyl, halo, chloro, and fluoro.

-   In some embodiments of the compound of formula AA, -   the substituted ring B is

and R⁶ is selected from:

C₁-C₆ alkyl, C₁-C₆ alkyl substituted with one or more halo, C₁-C₆ alkoxy, C₁-C₆ alkoxy substituted with one or more halo, C₃-C₇ cycloalkyl, halo, and cyano.

-   In some embodiments of the compound of formula AA, -   the substituted ring B is

and R⁶ is selected from:

isopropyl, ethyl, methyl, trifluoromethyl, trifluoromethoxy, cyclopropyl, halo, chloro, and fluoro.

-   In some embodiments of the compound of formula AA, -   the substituted ring B is

and R⁶ is selected from:

C₁-C₆ alkyl, C₁-C₆ alkyl substituted with one or more halo, C₁-C₆ alkoxy, C₁-C₆ alkoxy substituted with one or more halo, C₃-C₇ cycloalkyl, halo, and cyano.

-   In some embodiments of the compound of formula AA, -   the substituted ring B is

and R⁶ is selected from:

isopropyl, ethyl, methyl, trifluoromethyl, trifluoromethoxy, cyclopropyl, halo, chloro, and fluoro.

-   In some embodiments of the compound of formula AA, -   the substituted ring B is

and R⁶ is selected from:

C₁-C₆ alkyl, C₁-C₆ alkyl substituted with one or more halo, C₁-C₆ alkoxy, C₁-C₆ alkoxy substituted with one or more halo, C₃-C₇ cycloalkyl, halo, and cyano.

-   In some embodiments of the compound of formula AA, -   the substituted ring B is

and R⁶ is selected from:

isopropyl, ethyl, methyl, trifluoromethyl, trifluoromethoxy, cyclopropyl, halo, chloro, and fluoro.

In some embodiments, the substituted ring B is

and each R⁶ is independently selected from the group consisting of: C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl.

In some embodiments, the substituted ring B is

and each R⁶ is independently selected from the group consisting of: C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₃-C₇ cycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, or oxo.

In some embodiments, the substituted ring B is

wherein each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl,

-   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to     6-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein R⁷ is independently selected from C₁-C₆ alkyl, C₁-C₆         haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆         alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl,         OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to         7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered         heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and         4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is         optionally substituted with one to two C₁-C₆ alkoxy; -   or R⁶ and R⁷, taken together with the atoms connecting them,     independently form C₄-C₇ carbocyclic ring or at least one     5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms     independently selected from O, N, and S, wherein the carbocyclic     ring or heterocyclic ring is optionally independently substituted     with one or more substituents independently selected from hydroxy,     halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the substituted ring B is

wherein each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl,

-   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to     6-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein R⁷ is independently selected from C₁-C₆ alkyl, C₁-C₆         haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆         alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl,         OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to         7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered         heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and         4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is         optionally substituted with one to two C₁-C₆ alkoxy; -   or R⁶ and R⁷, taken together with the atoms connecting them,     independently form C₄-C₇ carbocyclic ring or at least one     5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms     independently selected from O, N, and S, wherein the carbocyclic     ring or heterocyclic ring is optionally independently substituted     with one or more substituents independently selected from hydroxy,     halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     C₆-C₁₀ aryl, and CONR⁸R⁹.     -   In some embodiments, the substituted ring B is

wherein each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl,

-   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to     6-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein R⁷ is independently selected from C₁-C₆ alkyl, C₁-C₆         haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆         alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl,         OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to         7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered         heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and         4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is         optionally substituted with one to two C₁-C₆ alkoxy.     -   In some embodiments, the substituted ring B is

wherein each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl,

-   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to     6-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein each R⁷ is independently selected from C₁-C₆ alkyl,         C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN,         COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆         alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3-         to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered         heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and         4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is         optionally substituted with one to two C₁-C₆ alkoxy; -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₇ carbocyclic ring or at least one 5-to-7-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆     alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.     -   In some embodiments, the substituted ring B is

wherein each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl,

-   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to     6-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein each R⁷ is independently selected from C₁-C₆ alkyl,         C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN,         COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆         alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3-         to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered         heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and         4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is         optionally substituted with one to two C₁-C₆ alkoxy; -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together     with the atoms connecting them, independently form at least one     C₄-C₇ carbocyclic ring or at least one 5-to-7-membered heterocyclic     ring containing 1 or 2 heteroatoms independently selected from O, N,     and S, wherein the carbocyclic ring or heterocyclic ring is     optionally independently substituted with one or more substituents     independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆     alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In some embodiments, the substituted ring B is

wherein each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl,

-   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to     6-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein each R⁷ is independently selected from C₁-C₆ alkyl,         C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN,         COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆         alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3-         to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered         heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and         4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is         optionally substituted with one to two C₁-C₆ alkoxy;

or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₇ carbocyclic ring or at least one 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

-   -   In some embodiments, the substituted ring B is

wherein each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl,

-   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to     6-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein each R⁷ is independently selected from C₁-C₆ alkyl,         C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN,         COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆         alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3-         to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered         heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and         4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is         optionally substituted with one to two C₁-C₆ alkoxy; or R⁶ and         R⁷, taken together with the atoms connecting them, independently         form a C₄-C₇ carbocyclic ring or at least one 5-to-7-membered         heterocyclic ring containing 1 or 2 heteroatoms independently         selected from O, N, and S, wherein the carbocyclic ring or         heterocyclic ring is optionally independently substituted with         one or more substituents independently selected from hydroxy,         halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆         alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.     -   In some embodiments, the substituted ring B is

wherein each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl,

-   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to     6-membered heterocycloalkyl is optionally substituted with one or     more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein each R⁷ is independently selected from C₁-C₆ alkyl,         C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN,         COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆         alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3-         to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered         heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and         4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is         optionally substituted with one to two C₁-C₆ alkoxy;     -   or at least one pair of R⁶ and R⁷ on adjacent atoms, taken         together with the atoms connecting them, independently form at         least one C₄-C₇ carbocyclic ring or at least one 5-to-7-membered         heterocyclic ring containing 1 or 2 heteroatoms independently         selected from O, N, and S, wherein the carbocyclic ring or         heterocyclic ring is optionally independently substituted with         one or more substituents independently selected from hydroxy,         hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹,         CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, of the compound of formula AA, -   the substituted ring B is

and the two R⁶ are one of the following combinations:

-   -   (i) One R⁶ is C₁-C₆ alkyl, and the other R⁶ is C₁-C₆ alkyl         optionally substituted with one or more halo;     -   (ii) One R⁶ is C₁-C₆ alkyl and the other R⁶ is C₁-C₆ alkyl;     -   (iii) One R⁶ is C₁-C₆ alkyl, and the other R⁶ is C₁-C₆ alkyl         substituted with one or more halo;     -   (iv) One R⁶ is C₁-C₆ alkyl, and the other R⁶ is C₃-C₇         cycloalkyl;     -   (v) One R⁶ is C₁-C₆ alkyl, and the other R⁶ is halo;     -   (vi) One R⁶ is C₁-C₆ alkyl, and the other R⁶ is cyano;     -   (vii) One R⁶ is C₃-C₇ cycloalkyl, and the other R⁶ is C₃-C₇         cycloalkyl;     -   (viii) One R⁶ is C₃-C₇ cycloalkyl, and the other R⁶ is halo;     -   (ix) One R⁶ is cyclopropyl and the other R⁶ is halo;     -   (x) One R⁶ is C₁-C₆ alkyl, and the other R⁶ is C₁-C₆ alkoxy         optionally substituted with one or more halo;     -   (xi) One R⁶ is C₁-C₆ alkyl, and the other R⁶ is C₁-C₆ alkoxy;     -   (xii) One R⁶ is C₁-C₆ alkyl, and the other R⁶ is C₁-C₆ alkoxy         substituted with one or more halo;     -   (xiii) One R⁶ is halo, and the other R⁶ is C₁-C₆ haloalkyl;     -   (xiv) One R⁶ is halo, and the other R⁶ is C₁-C₆ haloalkoxy;     -   (xv) One R⁶ is C₁-C₆ alkoxy; and the other R⁶ is halo;     -   (xvi) One R⁶ is C₁-C₆ alkoxy; and the other R⁶ is chloro.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and the two R⁶ are one of the following combinations:

-   -   (i) One R⁶ is isopropyl; and the other R⁶ is methyl;     -   (ii) One R⁶ is isopropyl; and the other R⁶ is n-propyl;     -   (iii) One R⁶ is isopropyl; and the other R⁶ is isopropyl;     -   (iv) One R⁶ is isopropyl; and the other R⁶ is trifluoromethyl;     -   (v) One R⁶ is isopropyl; and the other R⁶ is cyclopropyl;     -   (vi) One R⁶ is isopropyl; and the other R⁶ is chloro;     -   (vii) One R⁶ is isopropyl; and the other R⁶ is fluoro;     -   (viii) One R⁶ is ethyl; and the other R⁶ is fluoro;     -   (ix) One R⁶ is isopropyl; and the other R⁶ is cyano;     -   (x) One R⁶ is cyclopropyl; and the other R⁶ is cyclopropyl;     -   (xi) One R⁶ is cyclopropyl; and the other R⁶ is chloro;     -   (xii) One R⁶ is cyclopropyl; and the other R⁶ is fluoro;     -   (xiii) One R⁶ is isopropyl; and the other R⁶ is methoxy;     -   (xiv) One R⁶ is isopropyl; and the other R⁶ is methoxy; or     -   (xv) One R⁶ is isopropyl; and the other R⁶ is trifluoromethoxy.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl optionally         substituted with one or more halo;     -   (ii) R⁶ is C₁-C₆ alkyl and R⁷ is C₁-C₆ alkyl;     -   (iii) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl substituted with         one or more halo;     -   (iv) R⁶ is C₁-C₆ alkyl, and R⁷ is C₃-C₇ cycloalkyl;     -   (v) R⁶ is C₁-C₆ alkyl, and R⁷ is halo;     -   (vi) R⁶ is C₁-C₆ alkyl, and R⁷ is cyano;     -   (vii) R⁶ is C₃-C₇ cycloalkyl, and R⁷ is C₃-C₇ cycloalkyl;     -   (viii) R⁶ is C₃-C₇ cycloalkyl, and R⁷ is halo;     -   (ix) R⁶ is cyclopropyl and R⁷ is halo;     -   (x) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy optionally         substituted with one or more halo;     -   (xi) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy;     -   (xii) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy substituted with         one or more halo;     -   (xiii) R⁶ is halo, and R⁷ is C₁-C₆ haloalkyl;     -   (xiv) R⁶ is halo, and R⁷ is C₁-C₆ haloalkoxy;     -   (xv) R⁶ is C₁-C₆ alkoxy; and R⁷ is halo;     -   (xvi) R⁶ is C₁-C₆ alkoxy; and R⁷ is chloro;     -   (xvii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkyl optionally         substituted with one or more halo;     -   (xviii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkyl substituted         with one or more halo;     -   (xix) R⁷ is C₁-C₆ alkyl, and R⁶ is C₃-C₇ cycloalkyl;     -   (xx) R⁷ is C₁-C₆ alkyl, and R⁶ is halo;     -   (xxi) R⁷ is C₁-C₆ alkyl and R⁶ is halo;     -   (xxii) R⁷ is C₁-C₆ alkyl, and R⁶ is cyano;     -   (xxiii) R⁷ is C₃-C₇ cycloalkyl, and R⁶ is C₃-C₇ cycloalkyl;     -   (xxiv) R⁷ is C₃-C₇ cycloalkyl, and R⁶ is halo;     -   (xxv) R⁷ is C₃-C₇ cycloalkyl and R⁶ is halo;     -   (xxvi) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy optionally         substituted with one or more halo;     -   (xxvii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy;     -   (xxviii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy substituted         with one or more halo;     -   (xxix) R⁷ is halo, and R⁶ is C₁-C₆ haloalkyl;     -   (xxx) R⁷ is halo, and R⁶ is C₁-C₆ haloalkoxy;     -   (xxxi) R⁷ is C₁-C₆ alkoxy; and R⁶ is halo; or     -   (xxxii) R⁷ is C₁-C₆ alkoxy; and R⁶ is chloro.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is isopropyl; and R⁷ is methyl;     -   (ii) R⁶ is isopropyl; and R⁷ is isopropyl;     -   (iii) R⁶ is isopropyl; and R⁷ is trifluoromethyl;     -   (iv) R⁶ is isopropyl; and R⁷ is cyclopropyl;     -   (v) R⁶ is isopropyl; and R⁷ is chloro;     -   (vi) R⁶ is isopropyl; and R⁷ is fluoro;     -   (vii) R⁶ is ethyl; and R⁷ is fluoro;     -   (viii) R⁶ is isopropyl; and R⁷ is cyano;     -   (ix) R⁶ is cyclopropyl; and R⁷ is cyclopropyl;     -   (x) R⁶ is cyclopropyl; and R⁷ is chloro;     -   (xi) R⁶ is cyclopropyl; and R⁷ is fluoro; R⁶ is isopropyl; and         R⁷ is methoxy;     -   (xii) R⁶ is isopropyl; and R⁷ is trifluoromethoxy;     -   (xiii) R⁶ is chloro; and R⁷ is trifluoromethyl;     -   (xiv) R⁶ is chloro; and R⁷ is trifluoromethoxy;     -   (xv) R⁷ is isopropyl; and R⁶ is methyl;     -   (xvi) R⁷ is isopropyl; and R⁶ is trifluoromethyl;     -   (xvii) R⁷ is isopropyl; and R⁶ is cyclopropyl;     -   (xviii) R⁷ is isopropyl; and R⁶ is chloro;     -   (xix) R⁷ is ethyl; and R⁶ is fluoro;     -   (xx) R⁷ is isopropyl; and R⁶ is cyano;     -   (xxi) R⁷ is cyclopropyl; and R⁶ is cyclopropyl;     -   (xxii) R⁷ is cyclopropyl; and R⁶ is chloro;     -   (xxiii) R⁷ is cyclopropyl; and R⁶ is fluoro;     -   (xxiv) R⁷ is isopropyl; and R⁶ is methoxy;     -   (xxv) R⁷ is isopropyl; and R⁶ is trifluoromethoxy;     -   (xxvi) R⁷ is chloro; and R⁶ is trifluoromethyl; or     -   (xxvii) R⁷ is chloro; and R⁶ is trifluoromethoxy.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl optionally         substituted with one or more halo;     -   (ii) R⁶ is C₁-C₆ alkyl and R⁷ is C₁-C₆ alkyl;     -   (iii) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl substituted with         one or more halo;     -   (iv) R⁶ is C₁-C₆ alkyl, and R⁷ is C₃-C₇ cycloalkyl;     -   (v) R⁶ is C₁-C₆ alkyl, and R⁷ is halo;     -   (vi) R⁶ is C₁-C₆ alkyl, and R⁷ is cyano;     -   (vii) R⁶ is C₃-C₇ cycloalkyl, and R⁷ is C₃-C₇ cycloalkyl;     -   (viii) R⁶ is C₃-C₇ cycloalkyl, and R⁷ is halo;     -   (ix) R⁶ is cyclopropyl and R⁷ is halo;     -   (x) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy optionally         substituted with one or more halo;     -   (xi) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy;     -   (xii) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy substituted with         one or more halo;     -   (xiii) R⁶ is halo, and R⁷ is C₁-C₆ haloalkyl;     -   (xiv) R⁶ is halo, and R⁷ is C₁-C₆ haloalkoxy;     -   (xv) R⁶ is C₁-C₆ alkoxy; and R⁷ is halo;     -   (xvi) R⁶ is C₁-C₆ alkoxy; and R⁷ is chloro;     -   (xvii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkyl optionally         substituted with one or more halo;     -   (xviii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkyl substituted         with one or more halo;     -   (xix) R⁷ is C₁-C₆ alkyl, and R⁶ is C₃-C₇ cycloalkyl;     -   (xx) R⁷ is C₁-C₆ alkyl, and R⁶ is halo;     -   (xxi) R⁷ is C₁-C₆ alkyl and R⁶ is halo;     -   (xxii) R⁷ is C₁-C₆ alkyl, and R⁶ is cyano;     -   (xxiii) R⁷ is C₃-C₇ cycloalkyl, and R⁶ is C₃-C₇ cycloalkyl;     -   (xxiv) R⁷ is C₃-C₇ cycloalkyl, and R⁶ is halo;     -   (xxv) R⁷ is C₃-C₇ cycloalkyl and R⁶ is halo;     -   (xxvi) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy optionally         substituted with one or more halo;     -   (xxvii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy;     -   (xxviii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy substituted         with one or more halo;     -   (xxix) R⁷ is halo, and R⁶ is C₁-C₆ haloalkyl;     -   (xxx) R⁷ is halo, and R⁶ is C₁-C₆ haloalkoxy;     -   (xxxi) R⁷ is C₁-C₆ alkoxy; and R⁶ is halo; or     -   (xxxii) R⁷ is C₁-C₆ alkoxy; and R⁶ is chloro.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is isopropyl; and R⁷ is methyl;     -   (ii) R⁶ is isopropyl; and R⁷ is isopropyl;     -   (iii) R⁶ is isopropyl; and R⁷ is trifluoromethyl;     -   (iv) R⁶ is isopropyl; and R⁷ is cyclopropyl;     -   (v) R⁶ is isopropyl; and R⁷ is chloro;     -   (vi) R⁶ is isopropyl; and R⁷ is fluoro;     -   (vii) R⁶ is ethyl; and R⁷ is fluoro;     -   (viii) R⁶ is isopropyl; and R⁷ is cyano;     -   (ix) R⁶ is cyclopropyl; and R⁷ is cyclopropyl;     -   (x) R⁶ is cyclopropyl; and R⁷ is chloro;     -   (xi) R⁶ is cyclopropyl; and R⁷ is fluoro;     -   (xii) R⁶ is isopropyl; and R⁷ is methoxy;     -   (xiii) R⁶ is isopropyl; and R⁷ is trifluoromethoxy;     -   (xiv) R⁶ is chloro; and R⁷ is trifluoromethyl;     -   (xv) R⁶ is chloro; and R⁷ is trifluoromethoxy;     -   (xvi) R⁷ is isopropyl; and R⁶ is methyl;     -   (xvii) R⁷ is isopropyl; and R⁶ is trifluoromethyl;     -   (xviii) R⁷ is isopropyl; and R⁶ is cyclopropyl;     -   (xix) R⁷ is isopropyl; and R⁶ is chloro;     -   (xx) R⁷ is ethyl; and R⁶ is fluoro;     -   (xxi) R⁷ is isopropyl; and R⁶ is cyano;     -   (xxii) R⁷ is cyclopropyl; and R⁶ is cyclopropyl;     -   (xxiii) R⁷ is cyclopropyl; and R⁶ is chloro;     -   (xxiv) R⁷ is cyclopropyl; and R⁶ is fluoro;     -   (xxv) R⁷ is isopropyl; and R⁶ is methoxy;     -   (xxvi) R⁷ is isopropyl; and R⁶ is trifluoromethoxy;     -   (xxvii) R⁷ is chloro; and R⁶ is trifluoromethyl; or     -   (xxviii) R⁷ is chloro; and R⁶ is trifluoromethoxy.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl optionally         substituted with one or more halo;     -   (ii) R⁶ is C₁-C₆ alkyl and R⁷ is C₁-C₆ alkyl;     -   (iii) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl substituted with         one or more halo;     -   (iv) R⁶ is C₁-C₆ alkyl, and R⁷ is C₃-C₇ cycloalkyl;     -   (v) R⁶ is C₁-C₆ alkyl, and R⁷ is halo;     -   (vi) R⁶ is C₁-C₆ alkyl, and R⁷ is cyano;     -   (vii) R⁶ is C₃-C₇ cycloalkyl, and R⁷ is C₃-C₇ cycloalkyl;     -   (viii) R⁶ is C₃-C₇ cycloalkyl, and R⁷ is halo;     -   (ix) R⁶ is cyclopropyl and R⁷ is halo;     -   (x) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy optionally         substituted with one or more halo;     -   (xi) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy;     -   (xii) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy substituted with         one or more halo;     -   (xiii) R⁶ is halo, and R⁷ is C₁-C₆ haloalkyl;     -   (xiv) R⁶ is halo, and R⁷ is C₁-C₆ haloalkoxy;     -   (xv) R⁶ is C₁-C₆ alkoxy; and R⁷ is halo;     -   (xvi) R⁶ is C₁-C₆ alkoxy; and R⁷ is chloro;     -   (xvii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkyl optionally         substituted with one or more halo;     -   (xviii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkyl substituted         with one or more halo;     -   (xix) R⁷ is C₁-C₆ alkyl, and R⁶ is C₃-C₇ cycloalkyl;     -   (xx) R⁷ is C₁-C₆ alkyl, and R⁶ is halo;     -   (xxi) R⁷ is C₁-C₆ alkyl and R⁶ is halo;     -   (xxii) R⁷ is C₁-C₆ alkyl, and R⁶ is cyano;     -   (xxiii) R⁷ is C₃-C₇ cycloalkyl, and R⁶ is C₃-C₇ cycloalkyl;     -   (xxiv) R⁷ is C₃-C₇ cycloalkyl, and R⁶ is halo;     -   (xxv) R⁷ is C₃-C₇ cycloalkyl and R⁶ is halo;     -   (xxvi) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy optionally         substituted with one or more halo;     -   (xxvii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy;     -   (xxviii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy substituted         with one or more halo;     -   (xxix) R⁷ is halo, and R⁶ is C₁-C₆ haloalkyl;     -   (xxx) R⁷ is halo, and R⁶ is C₁-C₆ haloalkoxy;     -   (xxxi) R⁷ is C₁-C₆ alkoxy; and R⁶ is halo; or     -   (xxxii) R⁷ is C₁-C₆ alkoxy; and R⁶ is chloro;     -   (xxxiii) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a C₄-C₆ aliphatic carbocyclic ring         optionally substituted with one or more hydroxy, oxo, or C₁-C₆         alkyl; or     -   (xxxiv) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a 5-to-6-membered heterocyclic ring         containing 1 heteroatom independently selected from O, N, and S,         wherein the heterocyclic ring optionally substituted with one or         more hydroxy, oxo, or C₁-C₆ alkyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is isopropyl; and R⁷ is methyl;     -   (ii) R⁶ is isopropyl; and R⁷ is isopropyl;     -   (iii) R⁶ is isopropyl; and R⁷ is trifluoromethyl;     -   (iv) R⁶ is isopropyl; and R⁷ is cyclopropyl;     -   (v) R⁶ is isopropyl; and R⁷ is chloro;     -   (vi) R⁶ is isopropyl; and R⁷ is fluoro;     -   (vii) R⁶ is ethyl; and R⁷ is fluoro;     -   (viii) R⁶ is isopropyl; and R⁷ is cyano;     -   (ix) R⁶ is cyclopropyl; and R⁷ is cyclopropyl;     -   (x) R⁶ is cyclopropyl; and R⁷ is chloro;     -   (xi) R⁶ is cyclopropyl; and R⁷ is fluoro;     -   (xii) R⁶ is isopropyl; and R⁷ is methoxy;     -   (xiii) R⁶ is isopropyl; and R⁷ is trifluoromethoxy;     -   (xiv) R⁶ is chloro; and R⁷ is trifluoromethyl;     -   (xv) R⁶ is chloro; and R⁷ is trifluoromethoxy;     -   (xvi) R⁷ is isopropyl; and R⁶ is methyl;     -   (xvii) R⁷ is isopropyl; and R⁶ is trifluoromethyl;     -   (xviii) R⁷ is isopropyl; and R⁶ is cyclopropyl;     -   (xix) R⁷ is isopropyl; and R⁶ is chloro;     -   (xx) R⁷ is ethyl; and R⁶ is fluoro;     -   (xxi) R⁷ is isopropyl; and R⁶ is cyano;     -   (xxii) R⁷ is cyclopropyl; and R⁶ is cyclopropyl;     -   (xxiii) R⁷ is cyclopropyl; and R⁶ is chloro;     -   (xxiv) R⁷ is cyclopropyl; and R⁶ is fluoro;     -   (xxv) R⁷ is isopropyl; and R⁶ is methoxy;     -   (xxvi) R⁷ is isopropyl; and R⁶ is trifluoromethoxy;     -   (xxvii) R⁷ is chloro; and R⁶ is trifluoromethyl;     -   (xxviii) R⁷ is chloro; and R⁶ is trifluoromethoxy;     -   (xxix) R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a C₄ aliphatic carbocyclic ring;     -   (xxx) R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a C₅ aliphatic carbocyclic ring;     -   (xxxi) R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a C₆ aliphatic carbocyclic ring;     -   (xxxii) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a 5-membered heterocyclic ring         containing 1 heteroatoms independently selected from O, N, and         S;     -   (xxxiii) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a 6-membered heterocyclic ring         containing 1 heteroatoms independently selected from O, N, and         S; or     -   (xxxiv) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a C₅ aliphatic carbocyclic ring.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl optionally         substituted with one or more halo;     -   (ii) R⁶ is C₁-C₆ alkyl and R⁷ is C₁-C₆ alkyl;     -   (iii) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl substituted with         one or more halo;     -   (iv) R⁶ is C₁-C₆ alkyl, and R⁷ is C₃-C₇ cycloalkyl;     -   (v) R⁶ is C₁-C₆ alkyl, and R⁷ is halo;     -   (vi) R⁶ is C₁-C₆ alkyl, and R⁷ is cyano;     -   (vii) R⁶ is C₃-C₇ cycloalkyl, and R⁷ is C₃-C₇ cycloalkyl;     -   (viii) R⁶ is C₃-C₇ cycloalkyl, and R⁷ is halo;     -   (ix) R⁶ is cyclopropyl and R⁷ is halo;     -   (x) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy optionally         substituted with one or more halo;     -   (xi) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy;     -   (xii) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy substituted with         one or more halo;     -   (xiii) R⁶ is halo, and R⁷ is C₁-C₆ haloalkyl;     -   (xiv) R⁶ is halo, and R⁷ is C₁-C₆ haloalkoxy;     -   (xv) R⁶ is C₁-C₆ alkoxy; and R⁷ is halo;     -   (xvi) R⁶ is C₁-C₆ alkoxy; and R⁷ is chloro;     -   (xvii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkyl optionally         substituted with one or more halo;     -   (xviii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkyl substituted         with one or more halo;     -   (xix) R⁷ is C₁-C₆ alkyl, and R⁶ is C₃-C₇ cycloalkyl;     -   (xx) R⁷ is C₁-C₆ alkyl, and R⁶ is halo;     -   (xxi) R⁷ is C₁-C₆ alkyl and R⁶ is halo;     -   (xxii) R⁷ is C₁-C₆ alkyl, and R⁶ is cyano;     -   (xxiii) R⁷ is C₃-C₇ cycloalkyl, and R⁶ is C₃-C₇ cycloalkyl;     -   (xxiv) R⁷ is C₃-C₇ cycloalkyl, and R⁶ is halo;     -   (xxv) R⁷ is C₃-C₇ cycloalkyl and R⁶ is halo;     -   (xxvi) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy optionally         substituted with one or more halo;     -   (xxvii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy;     -   (xxviii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy substituted         with one or more halo;     -   (xxix) R⁷ is halo, and R⁶ is C₁-C₆ haloalkyl;     -   (xxx) R⁷ is halo, and R⁶ is C₁-C₆ haloalkoxy;     -   (xxxi) R⁷ is C₁-C₆ alkoxy; and R⁶ is halo; or     -   (xxxii) R⁷ is C₁-C₆ alkoxy; and R⁶ is chloro.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl optionally         substituted with one or more halo;     -   (ii) R⁶ is C₁-C₆ alkyl and R⁷ is C₁-C₆ alkyl;     -   (iii) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl substituted with         one or more halo;     -   (iv) R⁶ is C₁-C₆ alkyl, and R⁷ is C₃-C₇ cycloalkyl;     -   (v) R⁶ is C₁-C₆ alkyl, and R⁷ is halo;     -   (vi) R⁶ is C₁-C₆ alkyl, and R⁷ is cyano;     -   (vii) R⁶ is C₃-C₇ cycloalkyl, and R⁷ is C₃-C₇ cycloalkyl;     -   (viii) R⁶ is C₃-C₇ cycloalkyl, and R⁷ is halo;     -   (ix) R⁶ is cyclopropyl and R⁷ is halo;     -   (x) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy optionally         substituted with one or more halo;     -   (xi) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy;     -   (xii) R⁶ is C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy substituted with         one or more halo;     -   (xiii) R⁶ is halo, and R⁷ is C₁-C₆ haloalkyl;     -   (xiv) R⁶ is halo, and R⁷ is C₁-C₆ haloalkoxy;     -   (xv) R⁶ is C₁-C₆ alkoxy; and R⁷ is halo;     -   (xvi) R⁶ is C₁-C₆ alkoxy; and R⁷ is chloro;     -   (xvii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkyl optionally         substituted with one or more halo;     -   (xviii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkyl substituted         with one or more halo;     -   (xix) R⁷ is C₁-C₆ alkyl, and R⁶ is C₃-C₇ cycloalkyl;     -   (xx) R⁷ is C₁-C₆ alkyl, and R⁶ is halo;     -   (xxi) R⁷ is C₁-C₆ alkyl and R⁶ is halo;     -   (xxii) R⁷ is C₁-C₆ alkyl, and R⁶ is cyano;     -   (xxiii) R⁷ is C₃-C₇ cycloalkyl, and R⁶ is C₃-C₇ cycloalkyl;     -   (xxiv) R⁷ is C₃-C₇ cycloalkyl, and R⁶ is halo;     -   (xxv) R⁷ is C₃-C₇ cycloalkyl and R⁶ is halo;     -   (xxvi) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy optionally         substituted with one or more halo;     -   (xxvii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy;     -   (xxviii) R⁷ is C₁-C₆ alkyl, and R⁶ is C₁-C₆ alkoxy substituted         with one or more halo;     -   (xxix) R⁷ is halo, and R⁶ is C₁-C₆ haloalkyl;     -   (xxx) R⁷ is halo, and R⁶ is C₁-C₆ haloalkoxy;     -   (xxxi) R⁷ is C₁-C₆ alkoxy; and R⁶ is halo;     -   (xxxii) R⁷ is C₁-C₆ alkoxy; and R⁶ is chloro;     -   (xxxiii) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a C₄-C₆ aliphatic carbocyclic ring         optionally substituted with one or more hydroxy, oxo, or C₁-C₆         alkyl; or     -   (xxxiv) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a 5-to-6-membered heterocyclic ring         containing 1 heteroatom independently selected from O, N, and S,         wherein the heterocyclic ring optionally substituted with one or         more hydroxy, oxo, or C₁-C₆ alkyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is isopropyl; and R⁷ is methyl;     -   (ii) R⁶ is isopropyl; and R⁷ is isopropyl;     -   (iii) R⁶ is isopropyl; and R⁷ is trifluoromethyl;     -   (iv) R⁶ is isopropyl; and R⁷ is cyclopropyl;     -   (v) R⁶ is isopropyl; and R⁷ is chloro;     -   (vi) R⁶ is isopropyl; and R⁷ is fluoro;     -   (vii) R⁶ is ethyl; and R⁷ is fluoro;     -   (viii) R⁶ is isopropyl; and R⁷ is cyano;     -   (ix) R⁶ is cyclopropyl; and R⁷ is cyclopropyl;     -   (x) R⁶ is cyclopropyl; and R⁷ is chloro;     -   (xi) R⁶ is cyclopropyl; and R⁷ is fluoro;     -   (xii) R⁶ is isopropyl; and R⁷ is methoxy;     -   (xiii) R⁶ is isopropyl; and R⁷ is trifluoromethoxy;     -   (xiv) R⁶ is chloro; and R⁷ is trifluoromethyl;     -   (xv) R⁶ is chloro; and R⁷ is trifluoromethoxy;     -   (xvi) R⁷ is isopropyl; and R⁶ is methyl;     -   (xvii) R⁷ is isopropyl; and R⁶ is trifluoromethyl;     -   (xviii) R⁷ is isopropyl; and R⁶ is cyclopropyl;     -   (xix) R⁷ is isopropyl; and R⁶ is chloro;     -   (xx) R⁷ is ethyl; and R⁶ is fluoro;     -   (xxi) R⁷ is isopropyl; and R⁶ is cyano;     -   (xxii) R⁷ is cyclopropyl; and R⁶ is cyclopropyl;     -   (xxiii) R⁷ is cyclopropyl; and R⁶ is chloro;     -   (xxiv) R⁷ is cyclopropyl; and R⁶ is fluoro;     -   (xxv) R⁷ is isopropyl; and R⁶ is methoxy;     -   (xxvi) R⁷ is isopropyl; and R⁶ is trifluoromethoxy;     -   (xxvii) R⁷ is chloro; and R⁶ is trifluoromethyl;     -   (xxviii) R⁷ is chloro; and R⁶ is trifluoromethoxy;     -   (xxix) R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a C₄ aliphatic carbocyclic ring;     -   (xxx) R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a C₅ aliphatic carbocyclic ring;     -   (xxxi) R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a C₆ aliphatic carbocyclic ring;     -   (xxxii) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a 5-membered heterocyclic ring         containing 1 heteroatoms independently selected from O, N, and         S;     -   (xxxiii) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a 6-membered heterocyclic ring         containing 1 heteroatoms independently selected from O, N, and         S; or     -   (xxxiv) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a C₅ aliphatic carbocyclic ring.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is isopropyl; and R⁷ is methyl;     -   (ii) R⁶ is isopropyl; and R⁷ is isopropyl;     -   (iii) R⁶ is isopropyl; and R⁷ is trifluoromethyl;     -   (iv) R⁶ is isopropyl; and R⁷ is cyclopropyl;     -   (v) R⁶ is isopropyl; and R⁷ is chloro;     -   (vi) R⁶ is isopropyl; and R⁷ is fluoro;     -   (vii) R⁶ is ethyl; and R⁷ is fluoro;     -   (viii) R⁶ is isopropyl; and R⁷ is cyano;     -   (ix) R⁶ is cyclopropyl; and R⁷ is cyclopropyl;     -   (x) R⁶ is cyclopropyl; and R⁷ is chloro;     -   (xi) R⁶ is cyclopropyl; and R⁷ is fluoro;     -   (xii) R⁶ is isopropyl; and R⁷ is methoxy;     -   (xiii) R⁶ is isopropyl; and R⁷ is trifluoromethoxy;     -   (xiv) R⁶ is chloro; and R⁷ is trifluoromethyl;     -   (xv) R⁶ is chloro; and R⁷ is trifluoromethoxy;     -   (xvi) R⁷ is isopropyl; and R⁶ is methyl;     -   (xvii) R⁷ is isopropyl; and R⁶ is trifluoromethyl;     -   (xviii) R⁷ is isopropyl; and R⁶ is cyclopropyl;     -   (xix) R⁷ is isopropyl; and R⁶ is chloro;     -   (xx) R⁷ is ethyl; and R⁶ is fluoro;     -   (xxi) R⁷ is isopropyl; and R⁶ is cyano;     -   (xxii) R⁷ is cyclopropyl; and R⁶ is cyclopropyl;     -   (xxiii) R⁷ is cyclopropyl; and R⁶ is chloro;     -   (xxiv) R⁷ is cyclopropyl; and R⁶ is fluoro;     -   (xxv) R⁷ is isopropyl; and R⁶ is methoxy;     -   (xxvi) R⁷ is isopropyl; and R⁶ is trifluoromethoxy;     -   (xxvii) R⁷ is chloro; and R⁶ is trifluoromethyl; or     -   (xxviii) R⁷ is chloro; and R⁶ is trifluoromethoxy.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl         optionally substituted with one or more halo;     -   (ii) each R⁶ is independently C₁-C₆ alkyl and R⁷ is C₁-C₆ alkyl;     -   (iii) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆         alkyl substituted with one or more halo;     -   (iv) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₃-C₇         cycloalkyl;     -   (v) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is halo;     -   (vi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is cyano;     -   (vii) each R⁶ is independently C₃-C₇ cycloalkyl, and R⁷ is C₃-C₇         cycloalkyl;     -   (viii) each R⁶ is independently C₃-C₇ cycloalkyl, and R⁷ is         halo;     -   (ix) each R⁶ is independently cyclopropyl and R⁷ is halo;     -   (x) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy         optionally substituted with one or more halo;     -   (xi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆         alkoxy;     -   (xii) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆         alkoxy substituted with one or more halo;     -   (xiii) each R⁶ is independently halo, and R⁷ is C₁-C₆ haloalkyl;     -   (xiv) each R⁶ is independently halo, and R⁷ is C₁-C₆ haloalkoxy;     -   (xv) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is halo;     -   (xvi) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is chloro;     -   (xvii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆         alkyl optionally substituted with one or more halo;     -   (xviii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆         alkyl substituted with one or more halo;     -   (xix) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₃-C₇         cycloalkyl;     -   (xx) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently halo;     -   (xxi) R⁷ is C₁-C₆ alkyl and each R⁶ is independently halo;     -   (xxii) R⁷ is C₁-C₆ alkyl, and R⁶ is cyano;     -   (xxiii) R⁷ is C₃-C₇ cycloalkyl, and each R⁶ is independently         C₃-C₇ cycloalkyl;     -   (xxiv) R⁷ is C₃-C₇ cycloalkyl, and each R⁶ is independently         halo;     -   (xxv) R⁷ is C₃-C₇ cycloalkyl and each R⁶ is independently halo;     -   (xxvi) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆         alkoxy optionally substituted with one or more halo;     -   (xxvii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆         alkoxy;     -   (xxviii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆         alkoxy substituted with one or more halo;     -   (xxix) R⁷ is halo, and each R⁶ is independently C₁-C₆ haloalkyl;     -   (xxx) R⁷ is halo, and each R⁶ is independently C₁-C₆ haloalkoxy;     -   (xxxi) R⁷ is C₁-C₆ alkoxy; and each R⁶ is independently halo;     -   (xxxii) R⁷ is C₁-C₆ alkoxy; and R⁶ is chloro;     -   (xxxiii) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a C₅ aliphatic carbocyclic ring;     -   (xxxiv) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a C₄-C₆ aliphatic carbocyclic ring         optionally substituted with one or more hydroxy, oxo, or C₁-C₆         alkyl; and one R⁶ is halo or cyano; or     -   (xxxv) R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a 5-to-6-membered heterocyclic ring         containing 1 heteroatom independently selected from O, N, and S,         wherein the heterocyclic ring optionally substituted with one or         more hydroxy, oxo, or C₁-C₆ alkyl; and one R⁶ is halo or cyano.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is isopropyl; and R⁷ is methyl;     -   (ii) each R⁶ is isopropyl; and R⁷ is isopropyl;     -   (iii) each R⁶ is isopropyl; and R⁷ is trifluoromethyl;     -   (iv) each R⁶ is isopropyl; and R⁷ is cyclopropyl;     -   (v) each R⁶ is isopropyl; and R⁷ is chloro;     -   (vi) each R⁶ is isopropyl; and R⁷ is fluoro;     -   (vii) each R⁶ is ethyl; and R⁷ is fluoro;     -   (viii) each R⁶ is isopropyl; and R⁷ is cyano;     -   (ix) each R⁶ is cyclopropyl; and R⁷ is cyclopropyl;     -   (x) each R⁶ is cyclopropyl; and R⁷ is chloro;     -   (xi) each R⁶ is cyclopropyl; and R⁷ is fluoro;     -   (xii) each R⁶ is isopropyl; and R⁷ is methoxy;     -   (xiii) each R⁶ is isopropyl; and R⁷ is trifluoromethoxy;     -   (xiv) each R⁶ is chloro; and R⁷ is trifluoromethyl;     -   (xv) each R⁶ is chloro; and R⁷ is trifluoromethoxy;     -   (xvi) R⁷ is isopropyl; and each R⁶ is methyl;     -   (xvii) R⁷ is isopropyl; and each R⁶ is trifluoromethyl;     -   (xviii) R⁷ is isopropyl; and each R⁶ is cyclopropyl;     -   (xix) R⁷ is isopropyl; and each R⁶ is chloro;     -   (xx) R⁷ is ethyl; and each R⁶ is fluoro;     -   (xxi) R⁷ is isopropyl; and each R⁶ is cyano;     -   (xxii) R⁷ is cyclopropyl; and each R⁶ is cyclopropyl;     -   (xxiii) R⁷ is cyclopropyl; and each R⁶ is chloro;     -   (xxiv) R⁷ is cyclopropyl; and each R⁶ is fluoro;     -   (xxv) R⁷ is isopropyl; and each R⁶ is methoxy;     -   (xxvi) R⁷ is isopropyl; and each R⁶ is trifluoromethoxy;     -   (xxvii) R⁷ is chloro; and each R⁶ is trifluoromethyl;     -   (xxviii) R⁷ is chloro; and each R⁶ is trifluoromethoxy;     -   (xxix) one R⁶ is isopropyl; the other R⁶ is trifluoromethyl; and         R⁷ is chloro;     -   (xxx) R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a C₄ aliphatic carbocyclic ring; and one R⁶         is fluoro, chloro, or cyano;     -   (xxxi) R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a C₅ aliphatic carbocyclic ring; and one R⁶         is fluoro, chloro, or cyano;     -   (xxxii) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a C₆ aliphatic carbocyclic ring; and         one R⁶ is fluoro, chloro, or cyano;     -   (xxxiii) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a 5-membered heterocyclic ring         containing 1 heteroatoms independently selected from O, N, and         S; and one R⁶ is fluoro, chloro, or cyano; or     -   (xxxiv) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a 6-membered heterocyclic ring         containing 1 heteroatoms independently selected from O, N, and         S; and one R⁶ is fluoro, chloro, or cyano.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl         optionally substituted with one or more halo;     -   (ii) each R⁶ is independently C₁-C₆ alkyl and R⁷ is C₁-C₆ alkyl;     -   (iii) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆         alkyl substituted with one or more halo;     -   (iv) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₃-C₇         cycloalkyl;     -   (v) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is halo;     -   (vi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is cyano;     -   (vii) each R⁶ is independently C₃-C₇ cycloalkyl, and R⁷ is C₃-C₇         cycloalkyl;     -   (viii) each R⁶ is independently C₃-C₇ cycloalkyl, and R⁷ is         halo;     -   (ix) each R⁶ is independently cyclopropyl and R⁷ is halo;     -   (x) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy         optionally substituted with one or more halo;     -   (xi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆         alkoxy;     -   (xii) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆         alkoxy substituted with one or more halo;     -   (xiii) each R⁶ is independently halo, and R⁷ is C₁-C₆ haloalkyl;     -   (xiv) each R⁶ is independently halo, and R⁷ is C₁-C₆ haloalkoxy;     -   (xv) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is halo;     -   (xvi) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is chloro;     -   (xvii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆         alkyl optionally substituted with one or more halo;     -   (xviii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆         alkyl substituted with one or more halo;     -   (xix) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₃-C₇         cycloalkyl;     -   (xx) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently halo;     -   (xxi) R⁷ is C₁-C₆ alkyl and each R⁶ is independently halo;     -   (xxii) R⁷ is C₁-C₆ alkyl, and R⁶ is cyano;     -   (xxiii) R⁷ is C₃-C₇ cycloalkyl, and each R⁶ is independently         C₃-C₇ cycloalkyl;     -   (xxiv) R⁷ is C₃-C₇ cycloalkyl, and each R⁶ is independently         halo;     -   (xxv) R⁷ is C₃-C₇ cycloalkyl and each R⁶ is independently halo;     -   (xxvi) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆         alkoxy optionally substituted with one or more halo;     -   (xxvii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆         alkoxy;     -   (xxviii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆         alkoxy substituted with one or more halo;     -   (xxix) R⁷ is halo, and each R⁶ is independently C₁-C₆ haloalkyl;     -   (xxx) R⁷ is halo, and each R⁶ is independently C₁-C₆ haloalkoxy;     -   (xxxi) R⁷ is C₁-C₆ alkoxy; and each R⁶ is independently halo; or     -   (xxxii) R⁷ is C₁-C₆ alkoxy; and R⁶ is chloro.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is isopropyl; and R⁷ is methyl;     -   (ii) each R⁶ is isopropyl; and R⁷ is isopropyl;     -   (iii) each R⁶ is isopropyl; and R⁷ is trifluoromethyl;     -   (iv) each R⁶ is isopropyl; and R⁷ is cyclopropyl;     -   (v) each R⁶ is isopropyl; and R⁷ is chloro;     -   (vi) each R⁶ is isopropyl; and R⁷ is fluoro;     -   (vii) each R⁶ is ethyl; and R⁷ is fluoro;     -   (viii) each R⁶ is isopropyl; and R⁷ is cyano;     -   (ix) each R⁶ is cyclopropyl; and R⁷ is cyclopropyl;     -   (x) each R⁶ is cyclopropyl; and R⁷ is chloro;     -   (xi) each R⁶ is cyclopropyl; and R⁷ is fluoro;     -   (xii) each R⁶ is isopropyl; and R⁷ is methoxy;     -   (xiii) each R⁶ is isopropyl; and R⁷ is trifluoromethoxy;     -   (xiv) each R⁶ is chloro; and R⁷ is trifluoromethyl;     -   (xv) each R⁶ is chloro; and R⁷ is trifluoromethoxy;     -   (xvi) R⁷ is isopropyl; and each R⁶ is methyl;     -   (xvii) R⁷ is isopropyl; and each R⁶ is trifluoromethyl;     -   (xviii) R⁷ is isopropyl; and each R⁶ is cyclopropyl;     -   (xix) R⁷ is isopropyl; and each R⁶ is chloro;     -   (xx) R⁷ is ethyl; and each R⁶ is fluoro;     -   (xxi) R⁷ is isopropyl; and each R⁶ is cyano;     -   (xxii) R⁷ is cyclopropyl; and each R⁶ is cyclopropyl;     -   (xxiii) R⁷ is cyclopropyl; and each R⁶ is chloro;     -   (xxiv) R⁷ is cyclopropyl; and each R⁶ is fluoro;     -   (xxv) R⁷ is isopropyl; and each R⁶ is methoxy;     -   (xxvi) R⁷ is isopropyl; and each R⁶ is trifluoromethoxy;     -   (xxvii) R⁷ is chloro; and each R⁶ is trifluoromethyl;     -   (xxviii) R⁷ is chloro; and each R⁶ is trifluoromethoxy; or     -   (xxix) one R⁶ is isopropyl; the other R⁶ is trifluoromethyl; and         R⁷ is chloro.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆ alkyl         optionally substituted with one or more halo;     -   (ii) R⁶ is C₁-C₆ alkyl and each R⁷ is independently C₁-C₆ alkyl;     -   (iii) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆         alkyl substituted with one or more halo;     -   (iv) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₃-C₇         cycloalkyl;     -   (v) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently halo;     -   (vi) R⁶ is C₁-C₆ alkyl, and R⁷ is cyano;     -   (vii) R⁶ is C₃-C₇ cycloalkyl, and each R⁷ is independently C₃-C₇         cycloalkyl;     -   (viii) R⁶ is C₃-C₇ cycloalkyl, and each R⁷ is independently         halo;     -   (ix) R⁶ is cyclopropyl and each R⁷ is independently halo;     -   (x) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆ alkoxy         optionally substituted with one or more halo;     -   (xi) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆         alkoxy;     -   (xii) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆         alkoxy substituted with one or more halo;     -   (xiii) R⁶ is halo, and each R⁷ is independently C₁-C₆ haloalkyl;     -   (xiv) R⁶ is halo, and each R⁷ is independently C₁-C₆ haloalkoxy;     -   (xv) R⁶ is C₁-C₆ alkoxy; and each R⁷ is independently halo;     -   (xvi) R⁶ is C₁-C₆ alkoxy; and R⁷ is chloro;     -   (xvii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆         alkyl optionally substituted with one or more halo;     -   (xviii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆         alkyl substituted with one or more halo;     -   (xix) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₃-C₇         cycloalkyl;     -   (xx) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is halo;     -   (xxi) each R⁷ is independently C₁-C₆ alkyl and R⁶ is halo;     -   (xxii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is cyano;     -   (xxiii) each R⁷ is independently C₃-C₇ cycloalkyl, and R⁶ is         C₃-C₇ cycloalkyl.     -   (xxiv) each R⁷ is independently C₃-C₇ cycloalkyl, and R⁶ is         halo;     -   (xxv) each R⁷ is independently C₃-C₇ cycloalkyl and R⁶ is halo;     -   (xxvi) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆         alkoxy optionally substituted with one or more halo;     -   (xxvii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆         alkoxy;     -   (xxviii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆         alkoxy substituted with one or more halo;     -   (xxix) each R⁷ is independently halo, and R⁶ is C₁-C₆ haloalkyl;     -   (xxx) each R⁷ is independently halo, and R⁶ is C₁-C₆ haloalkoxy;     -   (xxxi) each R⁷ is independently C₁-C₆ alkoxy; and R⁶ is halo;     -   (xxxii) each R⁷ is independently C₁-C₆ alkoxy; and R⁶ is chloro;     -   (xxxiii) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a C₅ aliphatic carbocyclic ring;     -   (xxxiv) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a C₄-C₆ aliphatic carbocyclic ring         optionally substituted with one or more hydroxy, oxo, or C₁-C₆         alkyl; or     -   (xxxv) R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a 5-to-6-membered heterocyclic ring         containing 1 heteroatom independently selected from O, N, and S,         wherein the heterocyclic ring optionally substituted with one or         more hydroxy, oxo, or C₁-C₆ alkyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is isopropyl; and each R⁷ is methyl;     -   (ii) R⁶ is isopropyl; and each R⁷ is isopropyl;     -   (iii) R⁶ is isopropyl; and each R⁷ is trifluoromethyl;     -   (iv) R⁶ is isopropyl; and each R⁷ is cyclopropyl;     -   (v) R⁶ is isopropyl; and each R⁷ is chloro;     -   (vi) R⁶ is isopropyl; and each R⁷ is fluoro;     -   (vii) R⁶ is ethyl; and each R⁷ is fluoro;     -   (viii) R⁶ is isopropyl; and each R⁷ is cyano;     -   (ix) R⁶ is cyclopropyl; and each R⁷ is cyclopropyl;     -   (x) R⁶ is cyclopropyl; and each R⁷ is chloro;     -   (xi) R⁶ is cyclopropyl; and each R⁷ is fluoro;     -   (xii) R⁶ is isopropyl; and R⁷ is methoxy;     -   (xiii) R⁶ is isopropyl; and each R⁷ is trifluoromethoxy;     -   (xiv) R⁶ is chloro; and each R⁷ is trifluoromethyl;     -   (xv) R⁶ is chloro; and each R⁷ is trifluoromethoxy;     -   (xvi) each R⁷ is isopropyl; and R⁶ is methyl;     -   (xvii) each R⁷ is isopropyl; and R⁶ is trifluoromethyl;     -   (xviii) each R⁷ is isopropyl; and R⁶ is cyclopropyl;     -   (xix) each R⁷ is isopropyl; and R⁶ is chloro;     -   (xx) each R⁷ is ethyl; and R⁶ is fluoro;     -   (xxi) each R⁷ is isopropyl; and R⁶ is cyano;     -   (xxii) each R⁷ is cyclopropyl; and R⁶ is cyclopropyl;     -   (xxiii) each R⁷ is cyclopropyl; and R⁶ is chloro;     -   (xxiv) each R⁷ is cyclopropyl; and R⁶ is fluoro;     -   (xxv) each R⁷ is isopropyl; and R⁶ is methoxy;     -   (xxvi) each R⁷ is isopropyl; and R⁶ is trifluoromethoxy;     -   (xxvii) each R⁷ is chloro; and R⁶ is trifluoromethyl;     -   (xxviii) each R⁷ is chloro; and R⁶ is trifluoromethoxy;     -   (xxix) R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a C₅ aliphatic carbocyclic ring; and one R⁷         is fluoro, chloro, or cyano;     -   (xxx) R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a C₄ aliphatic carbocyclic ring; and one R⁷         is fluoro, chloro, or cyano;     -   (xxxi) R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a C₆ aliphatic carbocyclic ring; and one R⁷         is fluoro, chloro, or cyano;     -   (xxxii) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a 5-membered heterocyclic ring         containing 1 heteroatoms independently selected from O, N, and         S; and one R⁷ is fluoro, chloro, or cyano; or     -   (xxxiii) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a 6-membered heterocyclic ring         containing 1 heteroatoms independently selected from O, N, and         S; and one R⁷ is fluoro, chloro, or cyano.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆ alkyl         optionally substituted with one or more halo;     -   (ii) R⁶ is C₁-C₆ alkyl and each R⁷ is independently C₁-C₆ alkyl;     -   (iii) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆         alkyl substituted with one or more halo;     -   (iv) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₃-C₇         cycloalkyl;     -   (v) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently halo;     -   (vi) R⁶ is C₁-C₆ alkyl, and R⁷ is cyano;     -   (vii) R⁶ is C₃-C₇ cycloalkyl, and each R⁷ is independently C₃-C₇         cycloalkyl;     -   (viii) R⁶ is C₃-C₇ cycloalkyl, and each R⁷ is independently         halo;     -   (ix) R⁶ is cyclopropyl and each R⁷ is independently halo;     -   (x) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆ alkoxy         optionally substituted with one or more halo;     -   (xi) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆         alkoxy;     -   (xii) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆         alkoxy substituted with one or more halo;     -   (xiii) R⁶ is halo, and each R⁷ is independently C₁-C₆ haloalkyl;     -   (xiv) R⁶ is halo, and each R⁷ is independently C₁-C₆ haloalkoxy;     -   (xv) R⁶ is C₁-C₆ alkoxy; and each R⁷ is independently halo;     -   (xvi) R⁶ is C₁-C₆ alkoxy; and R⁷ is chloro;     -   (xvii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆         alkyl optionally substituted with one or more halo;     -   (xviii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆         alkyl substituted with one or more halo;     -   (xix) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₃-C₇         cycloalkyl;     -   (xx) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is halo;     -   (xxi) each R⁷ is independently C₁-C₆ alkyl and R⁶ is halo;     -   (xxii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is cyano;     -   (xxiii) each R⁷ is independently C₃-C₇ cycloalkyl, and R⁶ is         C₃-C₇ cycloalkyl;     -   (xxiv) each R⁷ is independently C₃-C₇ cycloalkyl, and R⁶ is         halo;     -   (xxv) each R⁷ is independently C₃-C₇ cycloalkyl and R⁶ is halo;     -   (xxvi) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆         alkoxy optionally substituted with one or more halo;     -   (xxvii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆         alkoxy;     -   (xxviii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆         alkoxy substituted with one or more halo;     -   (xxix) each R⁷ is independently halo, and R⁶ is C₁-C₆ haloalkyl;     -   (xxx) each R⁷ is independently halo, and R⁶ is C₁-C₆ haloalkoxy;     -   (xxxi) each R⁷ is independently C₁-C₆ alkoxy; and R⁶ is halo;     -   (xxxii) each R⁶ is independently C₁-C₆ alkoxy; and R⁶ is chloro;     -   (xxxiii) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a

C₅ aliphatic carbocyclic ring;

-   -   (xxxiv) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a C₄-C₆ aliphatic carbocyclic ring         optionally substituted with one or more hydroxy, oxo, or C₁-C₆         alkyl; or     -   (xxxiv) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a 5-to-6-membered heterocyclic ring         containing 1 heteroatom independently selected from O, N, and S,         wherein the heterocyclic ring optionally substituted with one or         more hydroxy, oxo, or C₁-C₆ alkyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is isopropyl; and each R⁷ is methyl;     -   (ii) R⁶ is isopropyl; and each R⁷ is isopropyl;     -   (iii) R⁶ is isopropyl; and each R⁷ is trifluoromethyl;     -   (iv) R⁶ is isopropyl; and each R⁷ is cyclopropyl;     -   (v) R⁶ is isopropyl; and each R⁷ is chloro;     -   (vi) R⁶ is isopropyl; and each R⁷ is fluoro;     -   (vii) R⁶ is ethyl; and each R⁷ is fluoro;     -   (viii) R⁶ is isopropyl; and each R⁷ is cyano;     -   (ix) R⁶ is cyclopropyl; and each R⁷ is cyclopropyl;     -   (x) R⁶ is cyclopropyl; and each R⁷ is chloro;     -   (xi) R⁶ is cyclopropyl; and each R⁷ is fluoro;     -   (xii) R⁶ is isopropyl; and each R⁷ is methoxy;     -   (xiii) R⁶ is isopropyl; and each R⁷ is trifluoromethoxy;     -   (xiv) R⁶ is chloro; and each R⁷ is trifluoromethyl;     -   (xv) R⁶ is chloro; and each R⁷ is trifluoromethoxy;     -   (xvi) each R⁷ is isopropyl; and R⁶ is methyl;     -   (xvii) each R⁷ is isopropyl; and R⁶ is trifluoromethyl;     -   (xviii) each R⁷ is isopropyl; and R⁶ is cyclopropyl;     -   (xix) each R⁷ is isopropyl; and R⁶ is chloro;     -   (xx) each R⁷ is ethyl; and R⁶ is fluoro;     -   (xxi) each R⁷ is isopropyl; and R⁶ is cyano;     -   (xxii) each R⁷ is cyclopropyl; and R⁶ is cyclopropyl;     -   (xxiii) each R⁷ is cyclopropyl; and R⁶ is chloro;     -   (xxiv) each R⁷ is cyclopropyl; and R⁶ is fluoro;     -   (xxv) each R⁷ is isopropyl; and R⁶ is methoxy;     -   (xxvi) each R⁷ is isopropyl; and R⁶ is trifluoromethoxy;     -   (xxvii) each R⁷ is chloro; and R⁶ is trifluoromethyl;     -   (xxviii) each R⁷ is chloro; and R⁶ is trifluoromethoxy;     -   (xxix) R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a C₅ aliphatic carbocyclic ring; and one R⁷         is fluoro, chloro, or cyano;     -   (xxx) R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a C₄ aliphatic carbocyclic ring; and one R⁷         is fluoro, chloro, or cyano;     -   (xxxi) R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a

C₆ aliphatic carbocyclic ring; and one R⁷ is fluoro, chloro, or cyano;

-   -   (xxxii) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a 5-membered heterocyclic ring         containing 1 heteroatoms independently selected from O, N, and         S; and one R⁷ is fluoro, chloro, or cyano; or     -   (xxxiii) R⁶ and R⁷ on adjacent atoms taken together with the         atoms connecting them form a 6-membered heterocyclic ring         containing 1 heteroatoms independently selected from O, N, and         S; and one R⁷ is fluoro, chloro, or cyano.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl         optionally substituted with one or more halo;     -   (ii) each R⁶ is independently C₁-C₆ alkyl and R⁷ is C₁-C₆ alkyl;     -   (iii) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆         alkyl substituted with one or more halo;     -   (iv) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₃-C₇         cycloalkyl;     -   (v) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is halo;     -   (vi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is cyano;     -   (vii) each R⁶ is independently C₃-C₇ cycloalkyl, and R⁷ is C₃-C₇         cycloalkyl;     -   (viii) each R⁶ is independently C₃-C₇ cycloalkyl, and R⁷ is         halo;     -   (ix) each R⁶ is independently cyclopropyl and R⁷ is halo;     -   (x) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy         optionally substituted with one or more halo;     -   (xi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆         alkoxy;     -   (xii) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆         alkoxy substituted with one or more halo;     -   (xiii) each R⁶ is independently halo, and R⁷ is C₁-C₆ haloalkyl;     -   (xiv) each R⁶ is independently halo, and R⁷ is C₁-C₆ haloalkoxy;     -   (xv) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is halo;     -   (xvi) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is chloro;     -   (xvii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆         alkyl optionally substituted with one or more halo;     -   (xviii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆         alkyl substituted with one or more halo;     -   (xix) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₃-C₇         cycloalkyl;     -   (xx) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently halo;     -   (xxi) R⁷ is C₁-C₆ alkyl and each R⁶ is independently halo;     -   (xxii) R⁷ is C₁-C₆ alkyl, and R⁶ is cyano;     -   (xxiii) R⁷ is C₃-C₇ cycloalkyl, and each R⁶ is independently         C₃-C₇ cycloalkyl;     -   (xxiv) R⁷ is C₃-C₇ cycloalkyl, and each R⁶ is independently         halo;     -   (xxv) R⁷ is C₃-C₇ cycloalkyl and each R⁶ is independently halo;     -   (xxvi) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆         alkoxy optionally substituted with one or more halo;     -   (xxvii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆         alkoxy;     -   (xxviii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆         alkoxy substituted with one or more halo;     -   (xxix) R⁷ is halo, and each R⁶ is independently C₁-C₆ haloalkyl;     -   (xxx) R⁷ is halo, and each R⁶ is independently C₁-C₆ haloalkoxy;     -   (xxxi) R⁷ is C₁-C₆ alkoxy; and each R⁶ is independently halo; or     -   (xxxii) R⁷ is C₁-C₆ alkoxy; and R⁶ is chloro.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is isopropyl; and R⁷ is methyl;     -   (ii) each R⁶ is isopropyl; and R⁷ is isopropyl;     -   (iii) each R⁶ is isopropyl; and R⁷ is trifluoromethyl;     -   (iv) each R⁶ is isopropyl; and R⁷ is cyclopropyl;     -   (v) each R⁶ is isopropyl; and R⁷ is chloro;     -   (vi) each R⁶ is isopropyl; and R⁷ is fluoro;     -   (vii) each R⁶ is ethyl; and R⁷ is fluoro;     -   (viii) each R⁶ is isopropyl; and R⁷ is cyano;     -   (ix) each R⁶ is cyclopropyl; and R⁷ is cyclopropyl;     -   (x) each R⁶ is cyclopropyl; and R⁷ is chloro;     -   (xi) each R⁶ is cyclopropyl; and R⁷ is fluoro;     -   (xii) each R⁶ is isopropyl; and R⁷ is methoxy;     -   (xiii) each R⁶ is isopropyl; and R⁷ is trifluoromethoxy;     -   (xiv) each R⁶ is chloro; and R⁷ is trifluoromethyl;     -   (xv) each R⁶ is chloro; and R⁷ is trifluoromethoxy;     -   (xvi) R⁷ is isopropyl; and each R⁶ is methyl;     -   (xvii) R⁷ is isopropyl; and each R⁶ is trifluoromethyl;     -   (xviii) R⁷ is isopropyl; and each R⁶ is cyclopropyl;     -   (xix) R⁷ is isopropyl; and each R⁶ is chloro;     -   (xx) R⁷ is ethyl; and each R⁶ is fluoro;     -   (xxi) R⁷ is isopropyl; and each R⁶ is cyano;     -   (xxii) R⁷ is cyclopropyl; and each R⁶ is cyclopropyl;     -   (xxiii) R⁷ is cyclopropyl; and each R⁶ is chloro;     -   (xxiv) R⁷ is cyclopropyl; and each R⁶ is fluoro;     -   (xxv) R⁷ is isopropyl; and each R⁶ is methoxy;     -   (xxvi) R⁷ is isopropyl; and each R⁶ is trifluoromethoxy;     -   (xxvii) R⁷ is chloro; and each R⁶ is trifluoromethyl;     -   (xxviii) R⁷ is chloro; and each R⁶ is trifluoromethoxy; or     -   (xxix) one R⁶ is isopropyl; the other R⁶ is trifluoromethyl; and         R⁷ is chloro.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆ alkyl         optionally substituted with one or more halo;     -   (ii) R⁶ is C₁-C₆ alkyl and each R⁷ is independently C₁-C₆ alkyl;     -   (iii) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆         alkyl substituted with one or more halo;     -   (iv) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₃-C₇         cycloalkyl;     -   (v) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently halo;     -   (vi) R⁶ is C₁-C₆ alkyl, and R⁷ is cyano;     -   (vii) R⁶ is C₃-C₇ cycloalkyl, and each R⁷ is independently C₃-C₇         cycloalkyl;     -   (viii) R⁶ is C₃-C₇ cycloalkyl, and each R⁷ is independently         halo;     -   (ix) R⁶ is cyclopropyl and each R⁷ is independently halo;     -   (x) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆ alkoxy         optionally substituted with one or more halo;     -   (xi) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆         alkoxy;     -   (xii) R⁶ is C₁-C₆ alkyl, and each R⁷ is independently C₁-C₆         alkoxy substituted with one or more halo;     -   (xiii) R⁶ is halo, and each R⁷ is independently C₁-C₆ haloalkyl;     -   (xiv) R⁶ is halo, and each R⁷ is independently C₁-C₆ haloalkoxy;     -   (xv) R⁶ is C₁-C₆ alkoxy; and each R⁷ is independently halo;     -   (xvi) R⁶ is C₁-C₆ alkoxy; and R⁷ is chloro;     -   (xvii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆         alkyl optionally substituted with one or more halo;     -   (xviii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆         alkyl substituted with one or more halo;     -   (xix) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₃-C₇         cycloalkyl;     -   (xx) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is halo;     -   (xxi) each R⁷ is independently C₁-C₆ alkyl and R⁶ is halo;     -   (xxii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is cyano;     -   (xxiii) each R⁷ is independently C₃-C₇ cycloalkyl, and R⁶ is         C₃-C₇ cycloalkyl;     -   (xxiv) each R⁷ is independently C₃-C₇ cycloalkyl, and R⁶ is         halo;     -   (xxv) each R⁷ is independently C₃-C₇ cycloalkyl and R⁶ is halo;     -   (xxvi) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆         alkoxy optionally substituted with one or more halo;     -   (xxvii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆         alkoxy;     -   (xxviii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is C₁-C₆         alkoxy substituted with one or more halo;     -   (xxix) each R⁷ is independently halo, and R⁶ is C₁-C₆ haloalkyl;     -   (xxx) each R⁷ is independently halo, and R⁶ is C₁-C₆ haloalkoxy;     -   (xxxi) each R⁷ is independently C₁-C₆ alkoxy; and R⁶ is halo; or     -   (xxxii) each R⁷ is independently C₁-C₆ alkoxy; and R⁶ is chloro.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) R⁶ is isopropyl; and each R⁷ is methyl;     -   (ii) R⁶ is isopropyl; and each R⁷ is isopropyl;     -   (iii) R⁶ is isopropyl; and each R⁷ is trifluoromethyl;     -   (iv) R⁶ is isopropyl; and each R⁷ is cyclopropyl;     -   (v) R⁶ is isopropyl; and each R⁷ is chloro;     -   (vi) R⁶ is isopropyl; and each R⁷ is fluoro;     -   (vii) R⁶ is ethyl; and each R⁷ is fluoro;     -   (viii) R⁶ is isopropyl; and each R⁷ is cyano;     -   (ix) R⁶ is cyclopropyl; and each R⁷ is cyclopropyl;     -   (x) R⁶ is cyclopropyl; and each R⁷ is chloro;     -   (xi) R⁶ is cyclopropyl; and each R⁷ is fluoro;     -   (xii) R⁶ is isopropyl; and each R⁷ is methoxy;     -   (xiii) ;R⁶ is isopropyl; and each R⁷ is trifluoromethoxy;     -   (xiv) R⁶ is chloro; and each R⁷ is trifluoromethyl;     -   (xv) R⁶ is chloro; and each R⁷ is trifluoromethoxy;     -   (xvi) each R⁷ is isopropyl; and R⁶ is methyl;     -   (xvii) each R⁷ is isopropyl; and R⁶ is trifluoromethyl;     -   (xviii) each R⁷ is isopropyl; and R⁶ is cyclopropyl;     -   (xix) each R⁷ is isopropyl; and R⁶ is chloro;     -   (xx) each R⁷ is ethyl; and R⁶ is fluoro;     -   (xxi) each R⁷ is isopropyl; and R⁶ is cyano;     -   (xxii) each R⁷ is cyclopropyl; and R⁶ is cyclopropyl;     -   (xxiii) each R⁷ is cyclopropyl; and R⁶ is chloro;     -   (xxiv) each R⁷ is cyclopropyl; and R⁶ is fluoro;     -   (xxv) each R⁷ is isopropyl; and R⁶ is methoxy;     -   (xxvi) each R⁷ is isopropyl; and R⁶ is trifluoromethoxy;     -   (xxvii) each R⁷ is chloro; and R⁶ is trifluoromethyl; or     -   (xxviii) each R⁷ is chloro; and R⁶ is trifluoromethoxy.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkyl optionally substituted with one or         more halo;     -   (ii) each R⁶ is independently C₁-C₆ alkyl and each R⁷ is         independently C₁-C₆ alkyl;;     -   (iii) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkyl substituted with one or more halo;     -   (iv) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₃-C₇ cycloalkyl;     -   (v) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently halo;     -   (vi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is cyano;     -   (vii) each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is         independently C₃-C₇ cycloalkyl;     -   (viii) each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is         independently halo;     -   (ix) each R⁶ is independently cyclopropyl and each R⁷ is         independently halo;     -   (x) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkoxy optionally substituted with one or         more halo;     -   (xi) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkoxy;     -   (xii) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkoxy substituted with one or more halo;     -   (xiii) each R⁶ is independently halo, and each R⁷ is         independently C₁-C₆ haloalkyl;     -   (xiv) each R⁶ is independently halo, and each R⁷ is         independently C₁-C₆ haloalkoxy;     -   (xv) each R⁶ is independently C₁-C₆ alkoxy; and each R⁷ is         independently halo;     -   (xvi) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is chloro;     -   (xvii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkyl optionally substituted with one or         more halo;     -   (xviii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkyl substituted with one or more halo;     -   (xix) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₃-C₇ cycloalkyl;     -   (xx) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently halo;     -   (xxi) each R⁷ is independently C₁-C₆ alkyl and each R⁶ is         independently halo;     -   (xxii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is cyano;     -   (xxiii) each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶         is independently C₃-C₇ cycloalkyl     -   (xxiv) each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶ is         independently halo;     -   (xxv) each R⁷ is independently C₃-C₇ cycloalkyl and each R⁶ is         independently halo;     -   (xxvi) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkoxy optionally substituted with one or         more halo;     -   (xxvii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkoxy;     -   (xxviii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkoxy substituted with one or more halo;     -   (xxix) each R⁷ is independently halo, and each R⁶ is         independently C₁-C₆ haloalkyl;     -   (xxx) each R⁷ is independently halo, and each R⁶ is         independently C₁-C₆ haloalkoxy;     -   (xxxi) each R⁷ is independently C₁-C₆ alkoxy; and each R⁶ is         independently halo;     -   (xxxii) each R⁷ is independently C₁-C₆ alkoxy; and R⁶ is chloro;     -   (xxxiii) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a C₄-C₈ aliphatic carbocyclic         ring;     -   (xxxiv) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a C₄-C₆ aliphatic carbocyclic         ring optionally substituted with one or more hydroxy, oxo, or         C₁-C₆ alkyl;     -   (xxxv) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and one pair of one R⁶ and one R⁷ taken together with the         atoms connecting them form a C₄-C₆ aliphatic carbocyclic ring         optionally substituted with one or more hydroxy, oxo, or C₁-C₆         alkyl, and the other pair of one R⁶ and one R⁷ taken together         with the atoms connecting them form a 5-to-6-membered         heterocyclic ring containing 1 heteroatom independently selected         from O, N, and S, wherein the heterocyclic ring is optionally         substituted with one or more hydroxy, oxo, or C₁-C₆ alkyl; or     -   (xxxvi) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a 5-to-6-membered heterocyclic         ring containing 1 heteroatom independently selected from O, N,         and S, wherein the heterocyclic ring optionally substituted with         one or more hydroxy, oxo, or C₁-C₆ alkyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is isopropyl; and each R⁷ is methyl;     -   (ii) each R⁶ is isopropyl; and each R⁷ is isopropyl;     -   (iii) each R⁶ is isopropyl; and each R⁷ is trifluoromethyl;     -   (iv) each R⁶ is isopropyl; and each R⁷ is cyclopropyl;     -   (v) each R⁶ is isopropyl; and each R⁷ is chloro;     -   (vi) each R⁶ is isopropyl; and each R⁷ is fluoro;     -   (vii) each R⁶ is ethyl; and each R⁷ is fluoro;     -   (viii) each R⁶ is isopropyl; and each R⁷ is cyano;     -   (ix) each R⁶ is cyclopropyl; and each R⁷ is cyclopropyl;     -   (x) each R⁶ is cyclopropyl; and each R⁷ is chloro;     -   (xi) each R⁶ is cyclopropyl; and each R⁷ is fluoro;     -   (xii) each R⁶ is isopropyl; and each R⁷ is methoxy;     -   (xiii) each R⁶ is isopropyl; and each R⁷ is trifluoromethoxy;     -   (xiv) each R⁶ is chloro; and each R⁷ is trifluoromethyl;     -   (xv) each R⁶ is chloro; and each R⁷ is trifluoromethoxy;     -   (xvi) each R⁷ is isopropyl; and each R⁶ is methyl;     -   (xvii) each R⁷ is isopropyl; and each R⁶ is trifluoromethyl;     -   (xviii) each R⁷ is isopropyl; and each R⁶ is cyclopropyl;     -   (xix) each R⁷ is isopropyl; and each R⁶ is chloro;     -   (xx) each R⁷ is ethyl; and each R⁶ is fluoro;     -   (xxi) each R⁷ is isopropyl; and each R⁶ is cyano;     -   (xxii) each R⁷ is cyclopropyl; and each R⁶ is cyclopropyl;     -   (xxiii) each R⁷ is cyclopropyl; and each R⁶ is chloro;     -   (xxiv) each R⁷ is cyclopropyl; and each R⁶ is fluoro;     -   (xxv) each R⁷ is isopropyl; and each R⁶ is methoxy;     -   (xxvi) each R⁷ is isopropyl; and each R⁶ is trifluoromethoxy;     -   (xxvii) each R⁷ is chloro; and each R⁶ is trifluoromethyl;     -   (xxviii) each R⁷ is chloro; and each R⁶ is trifluoromethoxy;     -   (xxix) one R⁶ is isopropyl; the other R⁶ is trifluoromethyl; and         each R⁷ is chloro;     -   (xxx) each R⁶ is isopropyl; one R⁷ is fluoro; and the other R⁷         is cyano;     -   (xxxi) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a C₅ aliphatic carbocyclic ring;     -   (xxxii) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a C₄ aliphatic carbocyclic ring         optionally substituted with one or more hydroxy, oxo, or methyl;     -   (xxxiii) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a C₅ aliphatic carbocyclic ring         optionally substituted with one or more hydroxy, oxo, or methyl;     -   (xxxiv) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a C₆ aliphatic carbocyclic ring         optionally substituted with one or more hydroxy, oxo, or methyl;     -   (xxxv) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a 5-membered heterocyclic ring         containing 1 heteroatom independently selected from O, N, and S,         wherein the heterocyclic ring is optionally substituted with one         or more hydroxy, oxo, or methyl;     -   (xxxvi) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a 6-membered heterocyclic ring         containing 1 heteroatom independently selected from O, N, and S,         wherein the heterocyclic ring is optionally substituted with one         or more hydroxy, oxo, or methyl; or     -   (xxxvii) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, one pair of one R⁶ and one R⁷ taken together with the         atoms connecting them form a 5-membered heterocyclic ring         containing 1 heteroatom independently selected from O, N, and S,         wherein the heterocyclic ring is optionally substituted with one         or more hydroxy, oxo, or methyl, and the other pair of one R⁶         and one R⁷ taken together with the atoms connecting them form a         C₅ aliphatic carbocyclic ring optionally substituted with one or         more hydroxy, oxo, or methyl .

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkyl optionally substituted with one or         more halo;     -   (ii) each R⁶ is independently C₁-C₆ alkyl and each R⁷ is         independently C₁-C₆ alkyl;     -   (iii) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkyl substituted with one or more halo;     -   (iv) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₃-C₇ cycloalkyl;     -   (v) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently halo;     -   (vi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is cyano;     -   (vii) each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is         independently C₃-C₇ cycloalkyl;     -   (viii) each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is         independently halo;     -   (ix) each R⁶ is independently cyclopropyl and each R⁷ is         independently halo;     -   (x) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkoxy optionally substituted with one or         more halo;     -   (xi) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkoxy;     -   (xii) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkoxy substituted with one or more halo;     -   (xiii) each R⁶ is independently halo, and each R⁷ is         independently C₁-C₆ haloalkyl;     -   (xiv) each R⁶ is independently halo, and each R⁷ is         independently C₁-C₆ haloalkoxy;     -   (xv) each R⁶ is independently C₁-C₆ alkoxy; and each R⁷ is         independently halo;     -   (xvi) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is chloro;     -   (xvii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkyl optionally substituted with one or         more halo;     -   (xviii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkyl substituted with one or more halo;     -   (xix) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₃-C₇ cycloalkyl;     -   (xx) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently halo;     -   (xxi) each R⁷ is independently C₁-C₆ alkyl and each R⁶ is         independently halo;     -   (xxii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is cyano;     -   (xxiii) each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶         is independently C₃-C₇ cycloalkyl;     -   (xxiv) each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶ is         independently halo;     -   (xxv) each R⁷ is independently C₃-C₇ cycloalkyl and each R⁶ is         independently halo;     -   (xxvi) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkoxy optionally substituted with one or         more halo;     -   (xxvii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkoxy;     -   (xxviii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkoxy substituted with one or more halo;     -   (xxix) each R⁷ is independently halo, and each R⁶ is         independently C₁-C₆ haloalkyl;     -   (xxx) each R⁷ is independently halo, and each R⁶ is         independently C₁-C₆ haloalkoxy;     -   (xxxi) each R⁷ is independently C₁-C₆ alkoxy; and each R⁶ is         independently halo;     -   (xxxii) each R⁷ is independently C₁-C₆ alkoxy; and R⁶ is chloro;     -   (xxxiii) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a C₄-C₈ aliphatic carbocyclic         ring;     -   (xxxiv) two pairs, each of one R⁶ and one R⁷ on adjacent atoms         taken together with the atoms connecting them form a C₄-C₆         aliphatic carbocyclic ring optionally substituted with one or         more hydroxy, oxo, or C₁-C₆ alkyl; or     -   (xxxv) two pairs, each of one R⁶ and one R⁷ on adjacent atoms         taken together with the atoms connecting them form a         5-to-6-membered heterocyclic ring containing 1 heteroatom         independently selected from O, N, and S, wherein the         heterocyclic ring optionally substituted with one or more         hydroxy, oxo, or C₁-C₆ alkyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is isopropyl; and each R⁷ is methyl;     -   (ii) each R⁶ is isopropyl; and each R⁷ is isopropyl;     -   (iii) each R⁶ is isopropyl; and each R⁷ is trifluoromethyl;     -   (iv) each R⁶ is isopropyl; and each R⁷ is cyclopropyl;     -   (v) each R⁶ is isopropyl; and each R⁷ is chloro;     -   (vi) each R⁶ is isopropyl; and each R⁷ is fluoro;     -   (vii) each R⁶ is ethyl; and each R⁷ is fluoro;     -   (viii) each R⁶ is isopropyl; and each R⁷ is cyano;     -   (ix) each R⁶ is cyclopropyl; and each R⁷ is cyclopropyl;     -   (x) each R⁶ is cyclopropyl; and each R⁷ is chloro;     -   (xi) each R⁶ is cyclopropyl; and each R⁷ is fluoro;     -   (xii) each R⁶ is isopropyl; and each R⁷ is methoxy;     -   (xiii) each R⁶ is isopropyl; and each R⁷ is trifluoromethoxy;     -   (xiv) each R⁶ is chloro; and each R⁷ is trifluoromethyl;     -   (xv) each R⁶ is chloro; and each R⁷ is trifluoromethoxy;     -   (xvi) each R⁷ is isopropyl; and each R⁶ is methyl;     -   (xvii) each R⁷ is isopropyl; and each R⁶ is trifluoromethyl;     -   (xviii) each R⁷ is isopropyl; and each R⁶ is cyclopropyl;     -   (xix) each R⁷ is isopropyl; and each R⁶ is chloro;     -   (xx) each R⁷ is ethyl; and each R⁶ is fluoro;     -   (xxi) each R⁷ is isopropyl; and each R⁶ is cyano;     -   (xxii) each R⁷ is cyclopropyl; and each R⁶ is cyclopropyl;     -   (xxiii) each R⁷ is cyclopropyl; and each R⁶ is chloro;     -   (xxiv) each R⁷ is cyclopropyl; and each R⁶ is fluoro;     -   (xxv) each R⁷ is isopropyl; and each R⁶ is methoxy;     -   (xxvi) each R⁷ is isopropyl; and each R⁶ is trifluoromethoxy;     -   (xxvii) each R⁷ is chloro; and each R⁶ is trifluoromethyl;     -   (xxviii) each R⁷ is chloro; and each R⁶ is trifluoromethoxy;     -   (xxix) one R⁶ is isopropyl; the other R⁶ is trifluoromethyl; and         each R⁷ is chloro;     -   (xxx) each R⁶ is isopropyl; one R⁷ is fluoro; and the other R⁷         is cyano; or     -   (xxxi) two pairs, each of one R⁶ and one R⁷ on adjacent atoms         taken together with the atoms connecting them form a C₄         aliphatic carbocyclic ring optionally substituted with one or         more hydroxy, oxo, or methyl;     -   (xxxii) two pairs, each of one R⁶ and one R⁷ on adjacent atoms         taken together with the atoms connecting them form a C₅         aliphatic carbocyclic ring optionally substituted with one or         more hydroxy, oxo, or methyl;     -   (xxxiii) two pairs, each of one R⁶ and one R⁷ on adjacent atoms         taken together with the atoms connecting them form a C₆         aliphatic carbocyclic ring optionally substituted with one or         more hydroxy, oxo, or methyl;     -   (xxxiv) two pairs, each of one R⁶ and one R⁷ on adjacent atoms         taken together with the atoms connecting them form a 5-membered         heterocyclic ring containing 1 heteroatom independently selected         from O, N, and S, wherein the heterocyclic ring is optionally         substituted with one or more hydroxy, oxo, or methyl;     -   (xxxv) two pairs, each of one R⁶ and one R⁷ on adjacent atoms         taken together with the atoms connecting them form a 6-membered         heterocyclic ring containing 1 heteroatom independently selected         from O, N, and S, wherein the heterocyclic ring is optionally         substituted with one or more hydroxy, oxo, or methyl; or     -   (xxxvi) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a C₅ aliphatic carbocyclic ring.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkyl optionally substituted with one or         more halo;     -   (ii) each R⁶ is independently C₁-C₆ alkyl and each R⁷ is         independently C₁-C₆ alkyl;     -   (iii) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkyl substituted with one or more halo;     -   (iv) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₃-C₇ cycloalkyl;     -   (v) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently halo;     -   (vi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is cyano;     -   (vii) each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is         independently C₃-C₇ cycloalkyl;     -   (viii) each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is         independently halo;     -   (ix) each R⁶ is independently cyclopropyl and each R⁷ is         independently halo;     -   (x) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkoxy optionally substituted with one or         more halo;     -   (xi) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkoxy;     -   (xii) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkoxy substituted with one or more halo;     -   (xiii) each R⁶ is independently halo, and each R⁷ is         independently C₁-C₆ haloalkyl;     -   (xiv) each R⁶ is independently halo, and each R⁷ is         independently C₁-C₆ haloalkoxy;     -   (xv) each R⁶ is independently C₁-C₆ alkoxy; and each R⁷ is         independently halo;     -   (xvi) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is chloro;     -   (xvii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkyl optionally substituted with one or         more halo;     -   (xviii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkyl substituted with one or more halo;     -   (xix) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₃-C₇ cycloalkyl;     -   (xx) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently halo;     -   (xxi) each R⁷ is independently C₁-C₆ alkyl and each R⁶ is         independently halo;     -   (xxii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is cyano;     -   (xxiii) each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶         is independently C₃-C₇ cycloalkyl;     -   (xxiv) each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶ is         independently halo;     -   (xxv) each R⁷ is independently C₃-C₇ cycloalkyl and each R⁶ is         independently halo;     -   (xxvi) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkoxy optionally substituted with one or         more halo;     -   (xxvii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkoxy;     -   (xxviii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkoxy substituted with one or more halo;     -   (xxix) each R⁷ is independently halo, and each R⁶ is         independently C₁-C₆ haloalkyl;     -   (xxx) each R⁷ is independently halo, and each R⁶ is         independently C₁-C₆ haloalkoxy;     -   (xxxi) each R⁷ is independently C₁-C₆ alkoxy; and each R⁶ is         independently halo; or     -   (xxxii) each R⁷ is independently C₁-C₆ alkoxy; and R⁶ is chloro.

-   In some embodiments of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is isopropyl; and each R⁷ is methyl;     -   (ii) each R⁶ is isopropyl; and each R⁷ is isopropyl;     -   (iii) each R⁶ is isopropyl; and each R⁷ is trifluoromethyl;     -   (iv) each R⁶ is isopropyl; and each R⁷ is cyclopropyl;     -   (v) each R⁶ is isopropyl; and each R⁷ is chloro;     -   (vi) each R⁶ is isopropyl; and each R⁷ is fluoro;     -   (vii) each R⁶ is ethyl; and each R⁷ is fluoro;     -   (viii) each R⁶ is isopropyl; and each R⁷ is cyano;     -   (ix) each R⁶ is cyclopropyl; and each R⁷ is cyclopropyl;     -   (x) each R⁶ is cyclopropyl; and each R⁷ is chloro;     -   (xi) each R⁶ is cyclopropyl; and each R⁷ is fluoro;     -   (xii) each R⁶ is isopropyl; and each R⁷ is methoxy;     -   (xiii) each R⁶ is isopropyl; and each R⁷ is trifluoromethoxy;     -   (xiv) each R⁶ is chloro; and each R⁷ is trifluoromethyl;     -   (xv) each R⁶ is chloro; and each R⁷ is trifluoromethoxy;     -   (xvi) each R⁷ is isopropyl; and each R⁶ is methyl;     -   (xvii) each R⁷ is isopropyl; and each R⁶ is trifluoromethyl;     -   (xviii) each R⁷ is isopropyl; and each R⁶ is cyclopropyl;     -   (xix) each R⁷ is isopropyl; and each R⁶ is chloro;     -   (xx) each R⁷ is ethyl; and each R⁶ is fluoro;     -   (xxi) each R⁷ is isopropyl; and each R⁶ is cyano;     -   (xxii) each R⁷ is cyclopropyl; and each R⁶ is cyclopropyl;     -   (xxiii) each R⁷ is cyclopropyl; and each R⁶ is chloro;     -   (xxiv) each R⁷ is cyclopropyl; and each R⁶ is fluoro;     -   (xxv) each R⁷ is isopropyl; and each R⁶ is methoxy;     -   (xxvi) each R⁷ is isopropyl; and each R⁶ is trifluoromethoxy;     -   (xxvii) each R⁷ is chloro; and each R⁶ is trifluoromethyl;     -   (xxviii) each R⁷ is chloro; and each R⁶ is trifluoromethoxy;     -   (xxix) one R⁶ is isopropyl; the other R⁶ is trifluoromethyl; and         R⁷ is chloro; or     -   (xxx) R⁶ is isopropyl; one R⁷ is fluoro; and the other R⁷ is         cyano.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkyl optionally substituted with one or         more halo;     -   each R⁶ is independently C₁-C₆ alkyl and each R⁷ is         independently C₁-C₆ alkyl;     -   each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkyl substituted with one or more halo;     -   each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₃-C₇ cycloalkyl;     -   each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently halo;     -   each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is cyano;     -   each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is         independently C₃-C₇ cycloalkyl;     -   each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is         independently halo;     -   each R⁶ is independently cyclopropyl and each R⁷ is         independently halo;     -   each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkoxy optionally substituted with one or         more halo;     -   each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkoxy;     -   each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkoxy substituted with one or more halo;     -   each R⁶ is independently halo, and each R⁷ is independently         C₁-C₆ haloalkyl;     -   each R⁶ is independently halo, and each R⁷ is independently         C₁-C₆ haloalkoxy;     -   each R⁶ is independently C₁-C₆ alkoxy; and each R⁷ is         independently halo;     -   each R⁶ is independently C₁-C₆ alkoxy; and each R⁷ is chloro;     -   each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkyl optionally substituted with one or         more halo;     -   each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkyl substituted with one or more halo;     -   each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₃-C₇ cycloalkyl;     -   each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently halo;     -   each R⁷ is independently C₁-C₆ alkyl and each R⁶ is         independently halo;     -   each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is cyano;     -   each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶ is         independently C₃-C₇ cycloalkyl;     -   each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶ is         independently halo;     -   each R⁷ is independently C₃-C₇ cycloalkyl and each R⁶ is         independently halo;     -   each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkoxy optionally substituted with one or         more halo;     -   each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkoxy;     -   each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkoxy substituted with one or more halo;     -   each R⁷ is independently halo, and each R⁶ is independently         C₁-C₆ haloalkyl;     -   each R⁷ is independently halo, and each R⁶ is independently         C₁-C₆ haloalkoxy;     -   each R⁷ is independently C₁-C₆ alkoxy; and each R⁶ is         independently halo;     -   each R⁷ is independently C₁-C₆ alkoxy; and each R⁶ is chloro;

R⁶ and R⁷ on adjacent atoms taken together with the atoms connecting them form a C₄-C₆ aliphatic carbocyclic ring optionally substituted with one or more hydroxy, oxo, or C₁-C₆ alkyl; and one R⁶ is halo or cyano; or

-   -   R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a 5-to-6-membered heterocyclic ring         containing 1 heteroatom independently selected from O, N, and S,         wherein the heterocyclic ring optionally substituted with one or         more hydroxy, oxo, or C₁-C₆ alkyl; and one R⁶ is halo or cyano.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   each R⁶ is isopropyl; and each R⁷ is methyl;     -   each R⁶ is isopropyl; and each R⁷ is isopropyl;     -   each R⁶ is isopropyl; and each R⁷ is trifluoromethyl;     -   each R⁶ is isopropyl; and each R⁷ is cyclopropyl;     -   each R⁶ is isopropyl; and each R⁷ is chloro;     -   each R⁶ is isopropyl; and each R⁷ is fluoro;     -   each R⁶ is ethyl; and each R⁷ is fluoro;     -   each R⁶ is isopropyl; and each R⁷ is cyano;     -   each R⁶ is cyclopropyl; and each R⁷ is cyclopropyl;     -   each R⁶ is cyclopropyl; and each R⁷ is chloro;     -   each R⁶ is cyclopropyl; and each R⁷ is fluoro;     -   each R⁶ is isopropyl; and each R⁷ is methoxy;     -   each R⁶ is isopropyl; and each R⁷ is trifluoromethoxy;     -   each R⁶ is chloro; and each R⁷ is trifluoromethyl;     -   each R⁶ is chloro; and each R⁷ is trifluoromethoxy;     -   each R⁷ is isopropyl; and each R⁶ is methyl;     -   each R⁷ is isopropyl; and each R⁶ is trifluoromethyl;     -   each R⁷ is isopropyl; and each R⁶ is cyclopropyl;     -   each R⁷ is isopropyl; and each R⁶ is chloro;     -   each R⁷ is ethyl; and each R⁶ is fluoro;     -   each R⁷ is isopropyl; and each R⁶ is cyano;     -   each R⁷ is cyclopropyl; and each R⁶ is cyclopropyl;     -   each R⁷ is cyclopropyl; and each R⁶ is chloro;     -   each R⁷ is cyclopropyl; and each R⁶ is fluoro;     -   each R⁷ is isopropyl; and each R⁶ is methoxy;     -   each R⁷ is isopropyl; and each R⁶ is trifluoromethoxy;     -   each R⁷ is chloro; and each R⁶ is trifluoromethyl;     -   each R⁷ is chloro; and each R⁶ is trifluoromethoxy;     -   one R⁶ is isopropyl; the other R⁶ is trifluoromethyl; and each         R⁷ is chloro;     -   each R⁶ is isopropyl; one R⁷ is fluoro; and the other R⁷ is         cyano;     -   R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a C₄ aliphatic carbocyclic ring; and one R⁶         is chloro, fluoro, or cyano;     -   R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a C₅ aliphatic carbocyclic ring; and one R⁶         is chloro, fluoro, or cyano;     -   R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a C₆ aliphatic carbocyclic ring; and one R⁶         is chloro, fluoro, or cyano;     -   R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a 5-membered heterocyclic ring containing 1         heteroatoms independently selected from O, N, and S; and one R⁶         is chloro, fluoro, or cyano;     -   R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a 6-membered heterocyclic ring containing 1         heteroatoms independently selected from O, N, and S; and one R⁶         is chloro, fluoro, or cyano; or     -   R⁶ and R⁷ on adjacent atoms taken together with the atoms         connecting them form a C₅ aliphatic carbocyclic ring; and one R⁶         is chloro, fluoro, or cyano.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkyl optionally substituted with one or         more halo;     -   (ii) each R⁶ is independently C₁-C₆ alkyl and each R⁷ is         independently C₁-C₆ alkyl;     -   (iii) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkyl substituted with one or more halo;     -   (iv) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₃-C₇ cycloalkyl;     -   (v) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently halo;     -   (vi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is cyano;     -   (vii) each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is         independently C₃-C₇ cycloalkyl;     -   (viii) each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is         independently halo;     -   (ix) each R⁶ is independently cyclopropyl and each R⁷ is         independently halo;     -   (x) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkoxy optionally substituted with one or         more halo;     -   (xi) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkoxy;     -   (xii) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkoxy substituted with one or more halo;     -   (xiii) each R⁶ is independently halo, and each R⁷ is         independently C₁-C₆ haloalkyl;     -   (xiv) each R⁶ is independently halo, and each R⁷ is         independently C₁-C₆ haloalkoxy;     -   (xv) each R⁶ is independently C₁-C₆ alkoxy; and each R⁷ is         independently halo;     -   (xvi) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is chloro;     -   (xvii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkyl optionally substituted with one or         more halo;     -   (xviii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkyl substituted with one or more halo;     -   (xix) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₃-C₇ cycloalkyl;     -   (xx) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently halo;     -   (xxi) each R⁷ is independently C₁-C₆ alkyl and each R⁶ is         independently halo;     -   (xxii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is cyano;     -   (xxiii) each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶         is independently C₃-C₇ cycloalkyl;     -   (xxiv) each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶ is         independently halo;     -   (xxv) each R⁷ is independently C₃-C₇ cycloalkyl and each R⁶ is         independently halo;     -   (xxvi) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkoxy optionally substituted with one or         more halo;     -   (xxvii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkoxy;     -   (xxviii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkoxy substituted with one or more halo;     -   (xxix) each R⁷ is independently halo, and each R⁶ is         independently C₁-C₆ haloalkyl;     -   (xxx) each R⁷ is independently halo, and each R⁶ is         independently C₁-C₆ haloalkoxy;     -   (xxxi) each R⁷ is independently C₁-C₆ alkoxy; and each R⁶ is         independently halo; or     -   (xxxii) each R⁷ is independently C₁-C₆ alkoxy; and R⁶ is chloro.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is isopropyl; and each R⁷ is methyl;     -   (ii) each R⁶ is isopropyl; and each R⁷ is isopropyl;     -   (iii) each R⁶ is isopropyl; and each R⁷ is trifluoromethyl;     -   (iv) each R⁶ is isopropyl; and each R⁷ is cyclopropyl;     -   (v) each R⁶ is isopropyl; and each R⁷ is chloro;     -   (vi) each R⁶ is isopropyl; and each R⁷ is fluoro;     -   (vii) each R⁶ is ethyl; and each R⁷ is fluoro;     -   (viii) each R⁶ is isopropyl; and each R⁷ is cyano;     -   (ix) each R⁶ is cyclopropyl; and each R⁷ is cyclopropyl;     -   (x) each R⁶ is cyclopropyl; and each R⁷ is chloro;     -   (xi) each R⁶ is cyclopropyl; and each R⁷ is fluoro;     -   (xii) each R⁶ is isopropyl; and each R⁷ is methoxy;     -   (xiii) each R⁶ is isopropyl; and each R⁷ is trifluoromethoxy;     -   (xiv) each R⁶ is chloro; and each R⁷ is trifluoromethyl;     -   (xv) each R⁶ is chloro; and each R⁷ is trifluoromethoxy;     -   (xvi) each R⁷ is isopropyl; and each R⁶ is methyl;     -   (xvii) each R⁷ is isopropyl; and each R⁶ is trifluoromethyl;     -   (xviii) each R⁷ is isopropyl; and each R⁶ is cyclopropyl;     -   (xix) each R⁷ is isopropyl; and each R⁶ is chloro;     -   (xx) each R⁷ is ethyl; and each R⁶ is fluoro;     -   (xxi) each R⁷ is isopropyl; and each R⁶ is cyano;     -   (xxii) each R⁷ is cyclopropyl; and each R⁶ is cyclopropyl;     -   (xxiii) each R⁷ is cyclopropyl; and each R⁶ is chloro;     -   (xxiv) each R⁷ is cyclopropyl; and each R⁶ is fluoro;     -   (xxv) each R⁷ is isopropyl; and each R⁶ is methoxy;     -   (xxvi) each R⁷ is isopropyl; and each R⁶ is trifluoromethoxy;     -   (xxvii) each R⁷ is chloro; and each R⁶ is trifluoromethyl;     -   (xxviii) each R⁷ is chloro; and each R⁶ is trifluoromethoxy;     -   (xxix) one R⁶ is isopropyl; the other R⁶ is trifluoromethyl; and         each R⁷ is chloro; or     -   (xxx) each R⁶ is isopropyl; one R⁷ is fluoro; and the other R⁷         is cyano.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkyl optionally substituted with one or         more halo;     -   (ii) each R⁶ is independently C₁-C₆ alkyl and each R⁷ is         independently C₁-C₆ alkyl;     -   (iii) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkyl substituted with one or more halo;     -   (iv) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₃-C₇ cycloalkyl;     -   (v) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently halo;     -   (vi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is cyano;     -   (vii) each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is         independently C₃-C₇ cycloalkyl;     -   (viii) each R⁶ is independently C₃-C₇ cycloalkyl, and each R⁷ is         independently halo;     -   (ix) each R⁶ is independently cyclopropyl and each R⁷ is         independently halo;     -   (x) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkoxy optionally substituted with one or         more halo;     -   (xi) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkoxy;     -   (xii) each R⁶ is independently C₁-C₆ alkyl, and each R⁷ is         independently C₁-C₆ alkoxy substituted with one or more halo;     -   (xiii) each R⁶ is independently halo, and each R⁷ is         independently C₁-C₆ haloalkyl;     -   (xiv) each R⁶ is independently halo, and each R⁷ is         independently C₁-C₆ haloalkoxy;     -   (xv) each R⁶ is independently C₁-C₆ alkoxy; and each R⁷ is         independently halo;     -   (xvi) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is chloro;     -   (xvii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkyl optionally substituted with one or         more halo;     -   (xviii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkyl substituted with one or more halo;     -   (xix) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₃-C₇ cycloalkyl;     -   (xx) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently halo;     -   (xxi) each R⁷ is independently C₁-C₆ alkyl and each R⁶ is         independently halo;     -   (xxii) each R⁷ is independently C₁-C₆ alkyl, and R⁶ is cyano;     -   (xxiii) each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶         is independently C₃-C₇ cycloalkyl;     -   (xxiv) each R⁷ is independently C₃-C₇ cycloalkyl, and each R⁶ is         independently halo;     -   (xxv) each R⁷ is independently C₃-C₇ cycloalkyl and each R⁶ is         independently halo;     -   (xxvi) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkoxy optionally substituted with one or         more halo;     -   (xxvii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkoxy;     -   (xxviii) each R⁷ is independently C₁-C₆ alkyl, and each R⁶ is         independently C₁-C₆ alkoxy substituted with one or more halo;     -   (xxix) each R⁷ is independently halo, and each R⁶ is         independently C₁-C₆ haloalkyl;     -   (xxx) each R⁷ is independently halo, and each R⁶ is         independently C₁-C₆ haloalkoxy;     -   (xxxi) each R⁷ is independently C₁-C₆ alkoxy; and each R⁶ is         independently halo;     -   (xxxvi) each R⁷ is independently C₁-C₆ alkoxy; and R⁶ is chloro;     -   (xxxvii) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a C₄-C₆ aliphatic carbocyclic         ring optionally substituted with one or more hydroxy, oxo, or         C₁-C₆ alkyl;     -   (xxxii) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a 5-to-6-membered heterocyclic         ring containing 1 heteroatom independently selected from O, N,         and S, wherein the heterocyclic ring optionally substituted with         one or more hydroxy, oxo, or C₁-C₆ alkyl; or     -   (xxxiii) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, one pair of one R⁶ and one R⁷ taken together with the         atoms connecting them form a C₄-C₆ aliphatic carbocyclic ring         optionally substituted with one or more hydroxy, oxo, or C₁-C₆         alkyl, and the other pair of one R⁶ and one R⁷ taken together         with the atoms connecting them form a 5-to-6-membered         heterocyclic ring containing 1 heteroatom independently selected         from O, N, and S, wherein the heterocyclic ring optionally         substituted with one or more hydroxy, oxo, or C₁-C₆ alkyl.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is isopropyl; and each R⁷ is methyl;     -   (ii) each R⁶ is isopropyl; and each R⁷ is isopropyl;     -   (iii) each R⁶ is isopropyl; and each R⁷ is trifluoromethyl;     -   (iv) each R⁶ is isopropyl; and each R⁷ is cyclopropyl;     -   (v) each R⁶ is isopropyl; and each R⁷ is chloro;     -   (vi) each R⁶ is isopropyl; and each R⁷ is fluoro;     -   (vii) each R⁶ is ethyl; and each R⁷ is fluoro;     -   (viii) each R⁶ is isopropyl; and each R⁷ is cyano;     -   (ix) each R⁶ is cyclopropyl; and each R⁷ is cyclopropyl;     -   (x) each R⁶ is cyclopropyl; and each R⁷ is chloro;     -   (xi) each R⁶ is cyclopropyl; and each R⁷ is fluoro;     -   (xii) each R⁶ is isopropyl; and each R⁷ is methoxy;     -   (xiii) each R⁶ is isopropyl; and each R⁷ is trifluoromethoxy;     -   (xiv) each R⁶ is chloro; and each R⁷ is trifluoromethyl;     -   (xv) each R⁶ is chloro; and each R⁷ is trifluoromethoxy;     -   (xvi) each R⁷ is isopropyl; and each R⁶ is methyl;     -   (xvii) each R⁷ is isopropyl; and each R⁶ is trifluoromethyl;     -   (xviii) each R⁷ is isopropyl; and each R⁶ is cyclopropyl;     -   (xix) each R⁷ is isopropyl; and each R⁶ is chloro;     -   (xx) each R⁷ is ethyl; and each R⁶ is fluoro;     -   (xxi) each R⁷ is isopropyl; and each R⁶ is cyano;     -   (xxii) each R⁷ is cyclopropyl; and each R⁶ is cyclopropyl;     -   (xxiii) each R⁷ is cyclopropyl; and each R⁶ is chloro;     -   (xxiv) each R⁷ is cyclopropyl; and each R⁶ is fluoro;     -   (xxv) each R⁷ is isopropyl; and each R⁶ is methoxy;     -   (xxvi) each R⁷ is isopropyl; and each R⁶ is trifluoromethoxy;     -   (xxvii) R⁷ is chloro; and each R⁶ is trifluoromethyl;     -   (xxviii) R⁷ is chloro; and each R⁶ is trifluoromethoxy;     -   (xxix) one R⁶ is isopropyl; the other R⁶ is trifluoromethyl; and         R⁷ is chloro;     -   (xxx) R⁶ is isopropyl; one R⁷ is fluoro; and the other R⁷ is         cyano; two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a C₅ aliphatic carbocyclic ring;     -   (xxxi) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a C₄ aliphatic carbocyclic ring         optionally substituted with one or more hydroxy, oxo, or methyl;     -   (xxxii) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a C₅ aliphatic carbocyclic ring         optionally substituted with one or more hydroxy, oxo, or methyl;     -   (xxxiii) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a C₆ aliphatic carbocyclic ring         optionally substituted with one or more hydroxy, oxo, or methyl;     -   (xxxiv) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a 5-membered heterocyclic ring         containing 1 heteroatom independently selected from O, N, and S,         wherein the heterocyclic ring is optionally substituted with one         or more hydroxy, oxo, or methyl     -   (xxxv) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a 6-membered heterocyclic ring         containing 1 heteroatom independently selected from O, N, and S,         wherein the heterocyclic ring is optionally substituted with one         or more hydroxy, oxo, or methyl; or     -   (xxxvi) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, one pair of one R⁶ and one R⁷ taken together with the         atoms connecting them form a 5-membered heterocyclic ring         containing 1 heteroatom independently selected from O, N, and S,         wherein the heterocyclic ring is optionally substituted with one         or more hydroxy, oxo, or methyl, and the other pair of one R⁶         and one R⁷ taken together with the atoms connecting them form a         C₅ aliphatic carbocyclic ring optionally substituted with one or         more hydroxy, oxo, or methyl .

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkyl         optionally substituted with one or more halo;     -   (ii) each R⁶ is independently C₁-C₆ alkyl and R⁷ is C₁-C₆ alkyl;     -   (iii) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆         alkyl substituted with one or more halo;     -   (iv) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₃-C₇         cycloalkyl;     -   (v) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is halo;     -   (vi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is cyano;     -   (vii) each R⁶ is independently C₃-C₇ cycloalkyl, and R⁷ is C₃-C₇         cycloalkyl;     -   (viii) each R⁶ is independently C₃-C₇ cycloalkyl, and R⁷ is         halo;     -   (ix) each R⁶ is independently cyclopropyl and R⁷ is halo;     -   (x) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆ alkoxy         optionally substituted with one or more halo;     -   (xi) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆         alkoxy;     -   (xii) each R⁶ is independently C₁-C₆ alkyl, and R⁷ is C₁-C₆         alkoxy substituted with one or more halo;     -   (xiii) each R⁶ is independently halo, and R⁷ is C₁-C₆ haloalkyl;     -   (xiv) each R⁶ is independently halo, and R⁷ is C₁-C₆ haloalkoxy;     -   (xv) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is halo;     -   (xvi) each R⁶ is independently C₁-C₆ alkoxy; and R⁷ is chloro;     -   (xvii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆         alkyl optionally substituted with one or more halo;     -   (xviii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆         alkyl substituted with one or more halo;     -   (xix) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₃-C₇         cycloalkyl;     -   (xx) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently halo;     -   (xxi) R⁷ is C₁-C₆ alkyl and each R⁶ is independently halo;     -   (xxii) R⁷ is C₁-C₆ alkyl, and R⁶ is cyano;     -   (xxiii) R⁷ is C₃-C₇ cycloalkyl, and each R⁶ is independently         C₃-C₇ cycloalkyl;     -   (xxiv) R⁷ is C₃-C₇ cycloalkyl, and each R⁶ is independently         halo;     -   (xxv) R⁷ is C₃-C₇ cycloalkyl and each R⁶ is independently halo;     -   (xxvi) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆         alkoxy optionally substituted with one or more halo;     -   (xxvii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆         alkoxy;     -   (xxviii) R⁷ is C₁-C₆ alkyl, and each R⁶ is independently C₁-C₆         alkoxy substituted with one or more halo;     -   (xxix) R⁷ is halo, and each R⁶ is independently C₁-C₆ haloalkyl;     -   (xxx) R⁷ is halo, and each R⁶ is independently C₁-C₆ haloalkoxy;     -   (xxxi) R⁷ is C₁-C₆ alkoxy; and each R⁶ is independently halo;     -   (xxxii) R⁷ is C₁-C₆ alkoxy; and R⁶ is chloro;     -   (xxxiii) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a C₄-C₈ aliphatic carbocyclic         ring; and one R⁷ is halo;     -   (xxxiv) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a C₄-C₈ aliphatic carbocyclic         ring; and one R⁷ is cyano;     -   (xxxv) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a C₄-C₆ aliphatic carbocyclic         ring optionally substituted with one or more hydroxy, oxo, or         C₁-C₆ alkyl; and one R⁷ is halo or cyano;     -   (xxxvi) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a 5-to-6-membered heterocyclic         ring containing 1 heteroatom independently selected from O, N,         and S, wherein the heterocyclic ring optionally substituted with         one or more hydroxy, oxo, or C₁-C₆ alkyl; and one R⁷ is halo or         cyano; or     -   (xxxvii) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, one pair of one R⁶ and one R⁷ taken together with the         atoms connecting them form a C₄-C₆ aliphatic carbocyclic ring         optionally substituted with one or more hydroxy, oxo, or C₁-C₆         alkyl, and the other pair of one R⁶ and one R⁷ taken together         with the atoms connecting them form a 5-to-6-membered         heterocyclic ring containing 1 heteroatom independently selected         from O, N, and S, wherein the heterocyclic ring optionally         substituted with one or more hydroxy, oxo, or C₁-C₆ alkyl; and         one R⁷ is halo or cyano.

-   In some embodiments, of the compound of formula AA,

-   the substituted ring B is

and R⁶ and R⁷ are one of the following combinations:

-   -   (i) each R⁶ is isopropyl; and each R⁷ is methyl;     -   (ii) each R⁶ is isopropyl; and each R⁷ is isopropyl;     -   (iii) each R⁶ is isopropyl; and each R⁷ is trifluoromethyl;     -   (iv) each R⁶ is isopropyl; and each R⁷ is cyclopropyl;     -   (v) each R⁶ is isopropyl; and each R⁷ is chloro;     -   (vi) each R⁶ is isopropyl; and each R⁷ is fluoro;     -   (vii) each R⁶ is ethyl; and each R⁷ is fluoro;     -   (viii) each R⁶ is isopropyl; and each R⁷ is cyano;     -   (ix) each R⁶ is cyclopropyl; and each R⁷ is cyclopropyl;     -   (x) each R⁶ is cyclopropyl; and each R⁷ is chloro;     -   (xi) each R⁶ is cyclopropyl; and each R⁷ is fluoro;     -   (xii) each R⁶ is isopropyl; and each R⁷ is methoxy;     -   (xiii) each R⁶ is isopropyl; and each R⁷ is trifluoromethoxy;     -   (xiv) each R⁶ is chloro; and each R⁷ is trifluoromethyl;     -   (xv) each R⁶ is chloro; and each R⁷ is trifluoromethoxy;     -   (xvi) each R⁷ is isopropyl; and each R⁶ is methyl;     -   (xvii) each R⁷ is isopropyl; and each R⁶ is trifluoromethyl;     -   (xviii) each R⁷ is isopropyl; and each R⁶ is cyclopropyl;     -   (xix) each R⁷ is isopropyl; and each R⁶ is chloro;     -   (xx) each R⁷ is ethyl; and each R⁶ is fluoro;     -   (xxi) each R⁷ is isopropyl; and each R⁶ is cyano;     -   (xxii) each R⁷ is cyclopropyl; and each R⁶ is cyclopropyl;     -   (xxiii) each R⁷ is cyclopropyl; and each R⁶ is chloro;     -   (xxiv) each R⁷ is cyclopropyl; and each R⁶ is fluoro;     -   (xxv) each R⁷ is isopropyl; and each R⁶ is methoxy;     -   (xxvi) each R⁷ is isopropyl; and each R⁶ is trifluoromethoxy;     -   (xxvii) each R⁷ is chloro; and each R⁶ is trifluoromethyl;     -   (xxviii) each R⁷ is chloro; and each R⁶ is trifluoromethoxy;     -   (xxix) each R⁶ is isopropyl; two R⁷ are fluoro; and one R⁷ is         chloro;     -   (xxx) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a C₅ aliphatic carbocyclic ring;         and one R⁷ is chloro;     -   (xxxi) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a C₅ aliphatic carbocyclic ring;         and one R⁷ is fluoro;     -   (xxxii) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a C₄ aliphatic carbocyclic ring         optionally substituted with one or more hydroxy, oxo, or methyl;         and one R⁷ is fluoro or chloro;     -   (xxxiii) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a C₅ aliphatic carbocyclic ring         optionally substituted with one or more hydroxy, oxo, or methyl;         and one R⁷ is fluoro or chloro;     -   (xxxiv) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a C₆ aliphatic carbocyclic ring         optionally substituted with one or more hydroxy, oxo, or methyl;         and one R⁷ is fluoro or chloro;     -   (xxxv) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a 5-membered heterocyclic ring         containing 1 heteroatom independently selected from O, N, and S,         wherein the heterocyclic ring is optionally substituted with one         or more hydroxy, oxo, or methyl; and one R⁷ is fluoro or chloro;     -   (xxxvi) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, and each pair of one R⁶ and one R⁷ taken together with         the atoms connecting them form a 6-membered heterocyclic ring         containing 1 heteroatom independently selected from O, N, and S,         wherein the heterocyclic ring is optionally substituted with one         or more hydroxy, oxo, or methyl; and one R⁷ is fluoro or chloro;         or     -   (xxxvii) two pairs, each of one R⁶ and one R⁷, are on adjacent         atoms, one pair of one R⁶ and one R⁷ taken together with the         atoms connecting them form a 5-membered heterocyclic ring         containing 1 heteroatom independently selected from O, N, and S,         wherein the heterocyclic ring is optionally substituted with one         or more hydroxy, oxo, or methyl, and the other pair of one R⁶         and one R⁷ taken together with the atoms connecting them form a         C₅ aliphatic carbocyclic ring optionally substituted with one or         more hydroxy, oxo, or methyl ; and one R⁷ is fluoro or chloro.

Non-Limiting Combinations

-   In some embodiments, when ring A is phenyl, then R¹ and R² are each     independently selected from C₃ alkyl, C₅-C₆ alkyl, C₁-C₆ haloalkyl,     C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, F, I, CN, NO₂, COC₂-C₆ alkyl,     CO—C₆-C₁₀ aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆ alkyl,     CO₂C₃-C₈ cycloalkyl, OCOC₂-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl,     N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to     10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl),     NHCOC₂-C₆ alkynyl, NHCOOCC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹,     SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl,     C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein the     C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to 7-membered     heterocycloalkyl are optionally substituted with one or more     substituents each independently selected from hydroxy, halo, CN,     oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy         substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²         3- to 7-membered heterocycloalkyl is further optionally         independently substituted with one to three hydroxy, halo,         NR⁸R⁹, or oxo; wherein the 3- to 7-membered heterocycloalkyl,         C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl,         NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or one pair of R¹ and R² on adjacent atoms, taken together with the     atoms connecting them, independently form one monocyclic or bicyclic     C₄ or C₆-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5-     to-12-membered heterocyclic ring containing 1-3 heteroatoms     independently selected from O, N, and S, wherein the carbocyclic     ring or heterocyclic ring is optionally independently substituted     with one or more substituents each independently selected from     hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆     alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl,     OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl,     and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀     aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl,     and 3- to 10-membered heterocycloalkyl are optionally substituted     with one or more substituents each independently selected from     hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀     cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹; and -   R⁶ and R⁷ are each independently selected from a C₂-C₆ alkyl, C₂-C₆     haloalkyl, C₂-C₆ alkoxy, C₁-C₆ haloalkoxy, I, CN, NO₂, COC₁-C₆     alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl,     OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to     7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅,     SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl and 3- to     10-membered heterocycloalkyl, and C₂-C₆ alkenyl, -   wherein R⁶ and R⁷ are each optionally substituted with one or more     substituents independently selected from hydroxy, halo, CN, oxo,     C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3-     to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered     heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆     alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3-     to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy,     and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy     that R⁶ or R⁷ is substituted with is optionally substituted with one     or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is     optionally fused to a five- to -seven-membered carbocyclic ring or     heterocyclic ring containing one or two heteroatoms independently     selected from oxygen, sulfur and nitrogen;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or one pair of R⁶ and R⁷ on adjacent atoms, taken together with the     atoms connecting them, independently form at least one C₄-C₈     carbocyclic ring or at least one 5- to 8-membered heterocyclic ring     containing 1 or 2 heteroatoms and/or heteroatomic groups     independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, wherein     the selected heteroatoms and/or heteroatomic groups are cumulative     with the nitrogen atoms present in ring B, and wherein the     carbocyclic ring or heterocyclic ring is optionally independently     substituted with one or more substituents independently selected     from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy,     NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, R¹ and R² are each independently selected from     C₃ alkyl, C₅-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆     haloalkoxy, F, I, CN, NO₂, COC₂-C₆ alkyl, CO—C₆-C₁₀ aryl, CO(5- to     10-membered heteroaryl), CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl,     OCOC₂-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl),     OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂,     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆     alkynyl, NHCOOCC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆     alkyl, S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl, C₃-C₇     cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆     alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to 7-membered     heterocycloalkyl are optionally substituted with one or more     substituents each independently selected from hydroxy, halo, CN,     oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy         substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²         3- to 7-membered heterocycloalkyl is further optionally         independently substituted with one to three hydroxy, halo,         NR⁸R⁹, or oxo; wherein the 3- to 7-membered heterocycloalkyl,         C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl,         NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or one pair of R¹ and R² on adjacent atoms, taken together with the     atoms connecting them, independently form one monocyclic or bicyclic     C₄ or C₆-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5-     to-12-membered heterocyclic ring containing 1-3 heteroatoms     independently selected from O, N, and S, wherein the carbocyclic     ring or heterocyclic ring is optionally independently substituted     with one or more substituents each independently selected from     hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆     alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹,═NR¹⁰,CN, COOC₁-C₆ alkyl,     OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl,     and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀     aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl,     and 3- to 10-membered heterocycloalkyl are optionally substituted     with one or more substituents each independently selected from     hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀     cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹; and -   R⁶ and R⁷ are each independently selected from a C₂-C₆ alkyl, C₂-C₆     haloalkyl, C₂-C₆ alkoxy, C₁-C₆ haloalkoxy, I, CN, NO₂, COC₁-C₆     alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl,     OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to     7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅,     SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl and 3- to     10-membered heterocycloalkyl, and C₂-C₆ alkenyl, -   wherein R⁶ and R⁷ are each optionally substituted with one or more     substituents independently selected from hydroxy, halo, CN, oxo,     C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3-     to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered     heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆     alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3-     to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy,     and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy     that R⁶ or R⁷ is substituted with is optionally substituted with one     or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is     optionally fused to a five- to -seven-membered carbocyclic ring or     heterocyclic ring containing one or two heteroatoms independently     selected from oxygen, sulfur and nitrogen;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or one pair of R⁶ and R⁷ on adjacent atoms, taken together with the     atoms connecting them, independently form at least one C₄-C₈     carbocyclic ring or at least one 5- to 8-membered heterocyclic ring     containing 1 or 2 heteroatoms and/or heteroatomic groups     independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, wherein     the selected heteroatoms and/or heteroatomic groups are cumulative     with the nitrogen atoms present in ring B, and wherein the     carbocyclic ring or heterocyclic ring is optionally independently     substituted with one or more substituents independently selected     from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy,     NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments of the compound of Formula AA, when ring A is     pyridyl, then R¹ and R² are each independently selected from C₁-C₆     alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN,     NO₂, COC₁-C₆ alkyl, CO—C₆-C₁₀ aryl, CO(5- to 10-membered     heteroaryl), CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl,     OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to     7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, NH₂, NHC₂-C₆ alkyl, N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl,     NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to     7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, NHCOOCC₁-C₆ alkyl,     NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl,     S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl, C₃-C₇ cycloalkyl, and 3- to     7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₁-C₆     haloalkyl, C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl     are optionally substituted with one or more substituents each     independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl,     C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to     5-membered heterocycloalkyl, 5-membered heteroaryl, OCOC₁-C₆ alkyl,     OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to     7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,     NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered     heterocycloalkyl), and NHCOC₂-C₆ alkynyl;     -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy         substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²         3- to 7-membered heterocycloalkyl is further optionally         independently substituted with one to three hydroxy, halo,         NR⁸R⁹, or oxo;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or one pair of R¹ and R² on adjacent atoms, taken together with the     atoms connecting them, independently form one monocyclic or bicyclic     C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5-     to-12-membered heterocyclic ring containing 1-3 heteroatoms     independently selected from O, N, and S, wherein the carbocyclic     ring or heterocyclic ring is optionally independently substituted     with one or more substituents each independently selected from     hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆     alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl,     OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl,     and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀     aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl,     and 3- to 10-membered heterocycloalkyl are optionally substituted     with one or more substituents each independently selected from     hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀     cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹; and -   R⁶ and R⁷ are each independently selected from a C₂-C₆ alkyl, C₂-C₆     haloalkyl, C₂-C₆ alkoxy, C₁-C₆ haloalkoxy, I, CN, NO₂, COC₁-C₆     alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl,     OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to     7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅,     SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl and 3- to     10-membered heterocycloalkyl, and C₂-C₆ alkenyl, -   wherein R⁶ and R⁷ are each optionally substituted with one or more     substituents independently selected from hydroxy, halo, CN, oxo,     C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3-     to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered     heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆     alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3-     to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy,     and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy     that R⁶ or R⁷ is substituted with is optionally substituted with one     or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is     optionally fused to a five- to -seven-membered carbocyclic ring or     heterocyclic ring containing one or two heteroatoms independently     selected from oxygen, sulfur and nitrogen;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or one pair of R⁶ and R⁷ on adjacent atoms, taken together with the     atoms connecting them, independently form at least one C₄-C₈     carbocyclic ring or at least one 5- to 8-membered heterocyclic ring     containing 1 or 2 heteroatoms and/or heteroatomic groups     independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, wherein     the selected heteroatoms and/or heteroatomic groups are cumulative     with the nitrogen atoms present in ring B, and wherein the     carbocyclic ring or heterocyclic ring is optionally independently     substituted with one or more substituents independently selected     from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy,     NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments of the compound of Formula AA, R¹ and R² are     each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆     alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO—C₆-C₁₀     aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆ alkyl, CO₂C₃-C₈     cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered     heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5-     to 10-membered heteroaryl, NH₂, NHC₂-C₆ alkyl, N(C₁-C₆ alkyl)₂,     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆     alkynyl, NHCOOCC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆     alkyl, S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl, C₃-C₇     cycloalkyl, and 3- to 7-membered heterocycloalkyl, -   wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, and 3-     to 7-membered heterocycloalkyl are optionally substituted with one     or more substituents each independently selected from hydroxy, halo,     CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 5-membered heterocycloalkyl, 5-membered heteroaryl,     OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl),     OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀     aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered     heterocycloalkyl), and NHCOC₂-C₆ alkynyl;     -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy         substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²         3- to 7-membered heterocycloalkyl is further optionally         independently substituted with one to three hydroxy, halo,         NR⁸R⁹, or oxo;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or one pair of R¹ and R² on adjacent atoms, taken together with the     atoms connecting them, independently form one monocyclic or bicyclic     C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5-     to-12-membered heterocyclic ring containing 1-3 heteroatoms     independently selected from O, N, and S, wherein the carbocyclic     ring or heterocyclic ring is optionally independently substituted     with one or more substituents each independently selected from     hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆     alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl,     OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl,     and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀     aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl,     and 3- to 10-membered heterocycloalkyl are optionally substituted     with one or more substituents each independently selected from     hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀     cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹; and -   R⁶ and R⁷ are each independently selected from a C₂-C₆ alkyl, C₂-C₆     haloalkyl, C₂-C₆ alkoxy, C₁-C₆ haloalkoxy, I, CN, NO₂, COC₁-C₆     alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl,     OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to     7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅,     SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl and 3- to     10-membered heterocycloalkyl, and C₂-C₆ alkenyl, -   wherein R⁶ and R⁷ are each optionally substituted with one or more     substituents independently selected from hydroxy, halo, CN, oxo,     C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3-     to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered     heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆     alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3-     to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy,     and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy     that R⁶ or R⁷ is substituted with is optionally substituted with one     or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is     optionally fused to a five- to -seven-membered carbocyclic ring or     heterocyclic ring containing one or two heteroatoms independently     selected from oxygen, sulfur and nitrogen;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or one pair of R⁶ and R⁷ on adjacent atoms, taken together with the     atoms connecting them, independently form at least one C₄-C₈     carbocyclic ring or at least one 5- to 8-membered heterocyclic ring     containing 1 or 2 heteroatoms and/or heteroatomic groups     independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, wherein     the selected heteroatoms and/or heteroatomic groups are cumulative     with the nitrogen atoms present in ring B, and wherein the     carbocyclic ring or heterocyclic ring is optionally independently     substituted with one or more substituents independently selected     from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy,     NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹. -   In some embodiments, R¹ and R² are each independently selected from     C₃ alkyl, CS-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆     haloalkoxy, F, I, CN, NO₂, COC₂-C₆ alkyl, CO—C₆-C₁₀ aryl, CO(5- to     10-membered heteroaryl), CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl,     OCOC₂-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl),     OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, NH₂, NHC₂-C₆ alkyl, N(C₁-C₆ alkyl)₂,     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆     alkynyl, NHCOOCC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆     alkyl, S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆ alkyl, C₃-C₇     cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆     alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 3- to 7-membered     heterocycloalkyl are optionally substituted with one or more     substituents each independently selected from hydroxy, halo, CN,     oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl,     CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to     10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to     10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl),     NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered     heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆     alkynyl;     -   wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy         substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R²         3- to 7-membered heterocycloalkyl is further optionally         independently substituted with one to three hydroxy, halo,         NR⁸R⁹, or oxo;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or one pair of R¹ and R² on adjacent atoms, taken together with the     atoms connecting them, independently form one monocyclic or bicyclic     C₄ or C₆-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5-     to-12-membered heterocyclic ring containing 1-3 heteroatoms     independently selected from O, N, and S, wherein the carbocyclic     ring or heterocyclic ring is optionally independently substituted     with one or more substituents each independently selected from     hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆     alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹,═NR¹⁰,CN, COOC₁-C₆ alkyl,     OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl,     and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀     aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl,     and 3- to 10-membered heterocycloalkyl are optionally substituted     with one or more substituents each independently selected from     hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀     cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀     aryl, and CONR⁸R⁹; and -   R⁶ and R⁷ are each independently selected from a C₂-C₆ alkyl, C₂-C₆     haloalkyl, C₂-C₆ alkoxy, C₁-C₆ haloalkoxy, I, CN, NO₂, COC₁-C₆     alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl,     OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to     7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered     heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅,     SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl and 3- to     10-membered heterocycloalkyl, and C₂-C₆ alkenyl, -   wherein R⁶ and R⁷ are each optionally substituted with one or more     substituents independently selected from hydroxy, halo, CN, oxo,     C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3-     to 5-membered heterocycloalkyl, 5-membered heteroaryl, OCOC₁-C₆     alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to     7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl,     NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered     heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆     alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy that R⁶ or R⁷ is     substituted with is optionally substituted with one or more     hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is optionally     fused to a five- to -seven-membered carbocyclic ring or heterocyclic     ring containing one or two heteroatoms independently selected from     oxygen, sulfur and nitrogen;     -   wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5-         to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to         10-membered heteroaryl) and NHCO(3- to 7-membered         heterocycloalkyl) are optionally substituted with one or more         substituents independently selected from halo, C₁-C₆ alkyl, and         OC₁-C₆ alkyl; -   or one pair of R⁶ and R⁷ on adjacent atoms, taken together with the     atoms connecting them, independently form at least one C₄-C₈     carbocyclic ring or at least one 5- to 8-membered heterocyclic ring     containing 1 or 2 heteroatoms and/or heteroatomic groups     independently selected from O, NH, NR¹³, S, S(O), and S(O)₂, wherein     the selected heteroatoms and/or heteroatomic groups are cumulative     with the nitrogen atoms present in ring B, and wherein the     carbocyclic ring or heterocyclic ring is optionally independently     substituted with one or more substituents independently selected     from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy,     NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

[Combination 1]

In some embodiments, the optionally substituted ring A is

wherein R^(x) is selected from the group consisting of H and C₁-C₆ alkyl (e.g., methyl); Z¹ is selected from the group consisting of O, NH, and —CH₂— optionally substituted with 1-2 R²⁰; Z² is selected from the group consisting of NH and —CH₂— optionally substituted with 1-2 R²⁰; Z³ is selected from the group consisting of —CH₂— optionally substituted with 1-2 R²⁰, —CH₂CH₂— optionally substituted with 1-2 R²⁰, and —CH₂CH₂CH₂— optionally substituted with 1-2 R²⁰; R²⁰ is selected from the group consisting of hydroxy, halo (e.g., fluoro), oxo, C₁-C₆ alkyl (e.g., methyl or ethyl) optionally substituted with one R²¹, C₁-C₆ alkoxy (e.g., methoxy, ethoxy, or isopropoxy) optionally substituted with one R²¹, NR⁸R⁹, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or pyrrolidinyl) optionally substituted with one R²¹, or one pair of R²⁰ on the same atom, taken together with the atom connecting them, independently forms a monocyclic C₃-C₄ carbocyclic ring or a monocyclic 3- to 4-membered heterocyclic ring containing 1 O atom optionally substituted with OS(O)₂Ph; R²¹ is selected from the group consisting of halo (e.g., fluoro), NR⁸R⁹, C₂-C₆ alkynyl (e.g., ethynyl), and C₁-C₆ alkoxy (e.g., methoxy); R⁸ and R⁹ at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl (e.g., methyl or ethyl), COR¹³, and CO₂R¹³; R¹³ is selected from the group consisting of: C₁-C₆ alkyl (e.g., methyl or t-butyl) and C₁-C₆ haloalkyl (e.g., trifluoromethyl); and

-   the substituted ring B is selected from:

wherein

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and each pair of one R⁶ and one R⁷ taken together with the atoms connecting them independently form a C₄-C₇ carbocyclic ring or a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein each carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; and

the remaining R⁷ that is not taken with a R⁶ on adjacent atoms to form a C₄-C₇ carbocyclic ring or a 5- to 7-membered heterocyclic ring is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is optionally substituted with one to two C₁-C₆ alkoxy.

[Combination 2]

In some embodiments, the optionally substituted ring A is

wherein Z⁴ is selected from the group consisting of —CH₂—, —C(O)—, and NH; Z⁵ is selected from the group consisting of O, NH, N—CH₃, and —CH₂—; and

the substituted ring B is selected from:

wherein

two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and each pair of one R⁶ and one R⁷ taken together with the atoms connecting them independently form a C₄-C₇ carbocyclic ring or a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein each carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; and

the remaining R⁷ that is not taken with a R⁶ on adjacent atoms to form a C₄-C₇ carbocyclic ring or a 5- to 7-membered heterocyclic ring is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is optionally substituted with one to two C₁-C₆ alkoxy.

In some embodiments of [Combination 1] and [Combination 2], the substituted ring B is

In some embodiments of [Combination 1] and [Combination 2], the substituted ring B is

In some embodiments of [Combination 1] and [Combination 2], one pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₅ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In certain of these embodiments, the other pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₅ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

As non-limiting examples of the foregoing embodiments, the substituted ring B is selected from:

As further non-limiting examples, the substituted ring B is

In certain embodiments of [Combination 1] and [Combination 2] (when one pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₅ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹), the other pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₄ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹ (e.g., the substituted ring B is:

In some embodiments of [Combination 1] and [Combination 2], one pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₄ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.

In certain of these embodiments, the other pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₄ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹ (e.g., the substituted ring B is:

Additional Features of the Embodiments Herein

In some embodiments of the compound of Formula AA (e.g., Formula AA-1, Formula AA-2, Formula AA-3, Formula AA-4, or Formula AA-5), R⁶ is not CN.

In some embodiments, the compound of Formula AA is not a compound selected from the group consisting of:

In some embodiments, the compound of Formula AA is not a compound selected from the group consisting of:

In some embodiments the compound of any of the formulae herein is not a compound disclosed in EP 0173498, which is incorporated herein by reference in its entirety.

In some embodiments the compound of any of the formulae herein is not a compound disclosed in U.S. Pat. No. 4,666,506, which is incorporated herein by reference in its entirety.

In some embodiments, the compound of any of the formulae herein is not a compound disclosed in WO 2018225018, which is incorporated herein by reference in its entirety.

In some embodiments, the compound of any one of the formulae herein is not a compound disclosed in IN 201721020305, which is incorporated herein by reference in its entirety.

In some embodiments, the compound of Formula AA is not selected from the group consisting of:

In some embodiments, the compound of Formula AA is other than:

It is understood that the combination of variables in the formulae herein is such that the compounds are stable.

In some embodiments, provided herein is a compound that is selected from the group consisting of the compounds in Table 1:

TABLE 1 Cmpd # Structure 101’

101

102

103’

103

104

105

105a

105b

106

106a

106b

107

107a

107b

108

108a

108b

109

109a

109b

110

110a

110b

111

112

112a

112b

113

113a

113b

114

115

116

116a

116b

117

118

119

120

120a

120b

121

121a

121b

122

122a

122b

123

124

125

125a

125b

126

127

128

129

129a

129b

130

130a

130b

131

131a

131b

132

133

134

134a

134b

135

135a

135b

136

136a

136b

137

137a

137b

138

138a

138b

139

139a

139b

140

141

142

143

143a

143b

144

144a

144b

145

145a

145b

146

147

148

148a

148b

149

149a

149b

150

151a’

151b’

151

151a

151b

152

152a

152b

153

153a

153b

154

154a

154b

155

156

157

157a

157b

158

158a

158b

159

159a

159ba

159ab

160

161

161a

161b

162

163

164

165

165a

165b

166

167

167a

167b

168

168a

168b

170

170a

170b

171

171a

171b

172

172a

172b

173

173a

173b

174

174a

174b

176

176a

176b

177

177a

177b

178

178a

178b

179

179a

179b

180

180a

180b

181

181a

181b

182

182a

182b

183

183a

183b

184

185

185a

185b

186

186a

186b

187

187a

187b

188

188a

189a

189b

190

190a

190b

191

191a

191b

192

192a

192b

193

193a

193b

194

195

195a

195ba

195bb

195e

196

197

198

199 200 201 202

202a

202b

203

204

205

205a

205b

206

206a

206b

207 207a

207b

207bb

207aa

207b

208

209

210 211

212

212a

212b

213

214

215

216 217 218

219 220

220a

220b

221 223 223a 223b

225

225a

225b

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

0 260

261

262

263

264

265

266

267

268

269

270

and pharmaceutically acceptable salts thereof.

In some embodiments, provided herein is a compound that is selected from the group consisting of the compounds in the following table:

303

303a

303b

306

307

308

308a

308b

309

310

311

312

313

314

315

315b

315a

316

316a

316b

317

317ab

317aa

317bb

317ba

318

318a

318b

319

319ab

319ba

319aa

319bb

320

320a

320b

321

321b

321a

322

323

323ab

323aa

323bb

323ba

324

325

325a

325b

326

326b

326a

327

328b

328a

329

329a

329b

330

330a

330b

331

332

332a

332b

333

333a

333b

334

334ba

334bb

334aa

334ab

334b

334a

335

335b

335a

336

336a

336b

337

337a

337b

338

338a

338b

339

339a

339b

340

340a

340b

341

341b

341a

342

343

343a

343b

344

345

346

347

348

349

350

351

352

352b

352a

353

354

354a

354b

355

356

357

357a

357b

358

359

359a

359b

360ba

360bb

361b

361a

363b

363a

364a

364b

365a

365b

366a

366b

367a

367b

369a

369b

371a

371b

372a

372b

373a

373b

374a

374b

375

375a

375b

376

376a

376b

377

378

379

379a

379b

380

380a

380b

380c

380d

382

382a

382b

383

383a

383b

384a

384b

387a

387b

and pharmaceutically acceptable salts thereof.

In some embodiments, provided herein is a compound that is selected from the group consisting of the compounds in the following table:

401

402

403

404

404a

404b

405

406

407

408

409

409a

409b

410

411

411a

412

412a

413

413a

414

415

In some embodiments, provided herein is a compound that is selected from the group consisting of the compounds in the following table:

501 1

502 2

503 3

504 4

505 5

506 6

507 7

508 8

509 9

510 10

511 11

512 12

513 13

514 14

515 15

516 A1-2

517 A1-3

518 A1-4

519 A1-5

520 A1-6

521 A1-7

522 A2-2

523 A2-3

524 A2-4

525 A2-5

526 A2-6

527 A2-7

528 A3-2

529 A3-3

530 A3-4

531 A3-5

532 A3-6

533 A3-7

534 A4-2

535 A4-3

536 A4-4

537 A4-5

538 A4-6

539 A4-7

540 A5-2

541 A5-3

542 A5-4

543 A5-5

544 A5-6

545 A5-7

546 A6-2

547 A6-3

548 A6-4

549 A6-5

550 A6-6

551 A6-7

552 A7-2

553 A7-3

554 A7-4

555 A7-5

556 A7-6

557 A7-7

558 A8-2

559 A8-3

560 A8-4

561 A8-5

562 A8-6

563 A8-7

564 A9-2

565 A9-3

566 A9-4

567 A9-5

568 A9-6

569 A9-7

570 A10-2

571 A10-3

572 A10-4

573 A10-5

574 A10-6

575 A10-7

576 A11-2

577 A11-3

578 A11-4

579 A11-5

580 A11-6

581 A11-7

582 A12-2

583 A12-3

584 A12-4

585 A12-5

586 A12-6

587 A12-7

588 A13-2

589 A13-3

590 A13-4

591 A13-5

592 A13-6

593 A13-7

594 A14-2

595 A14-3

596 A14-4

597 A14-5

598 A14-6

599 A14-7

600 A15-2

601 A15-3

602 A15-4

603 A15-5

604 A15-6

605 A15-7

606 A16-2

607 A16-3

608 A16-4

609 A16-5

610 A16-6

611 A16-7

612 A17-2

613 A17-3

614 A17-4

615 A17-5

616 A17-6

617 A17-7

618 A18-2

A18-3

A18-4

A18-5

A18-6

A18-7

A19-2

A19-3

A19-4

A19-5

A19-6

A19-7

A20-2

A20-3

A20-4

A20-5

A20-6

A20-7

A21-2

A21-3

A21-4

A21-5

A21-6

A21-7

B1-2

B1-3

B1-5

B1-6

B2-2

B2-3

B2-5

B2-6

B3-2

B3-3

B3-5

B3-6

B4-2

B4-3

B4-5

B4-6

B5-2

B5-3

B5-5

B5-6

B6-2

B6-3

B6-5

B6-6

B7-2

B7-3

B7-5

B7-6

B8-2

B8-3

B8-5

B8-6

B9-2

B9-3

B9-5

B9-6

B10-2

B10-3

B10-5

B10-6

B11-2

B11-3

B11-5

B11-6

B12-2

B12-3

B12-5

B12-6

B13-2

B13-3

B13-5

B13-6

B14-2

B14-3

B14-5

B14-6

B15-2

B15-3

B15-5

B15-6

B16-2

B16-3

B16-5

B16-6

B17-2

B17-3

B17-5

B17-6

B18-2

B18-3

B18-5

B18-6

C1-2

C1-6

C2-2

C2-6

C3-2

C3-6

C4-2

C4-6

C5-2

C5-6

C6-2

C6-6

D1-2

D1-6

D2-2

D2-6

D3-2

D3-6

D4-2

D4-6

D4-2

D4-6

In some embodiments, provided herein is a compound that is selected from the group consisting of the compounds in Table 1C below:

TABLE 1C Cmpd # Structure 322a

322b

344a

344b

346a

346b

349a

349b

355a

355b

356a

356b

377a

377b

378a

378b

411b

411c

411d

411e

412b

413b

501a

501b

801

802

802a

802b

802c

803

803a

803b

804

804a

804b

805

805a

805b

806

806a

806b

807

808

808a

808b

809

809a

809b

810

810a

810b

811

811a

811b

812

812a

812b

813

813a

813b

814

814a

814b

815

815a

815b

816

817

817a

817b

818

818a

818b

819

819a

819b

819c

819d

820

820a

820b

821

821a

821b

822

822a

822b

823

824

825

826

826a

826b

826c

826d

826e

826f

827a

828

828a

828b

829

829a

829b

829c

830

831

832

832a

832b

833

833a

833b

834

834a

834b

835

835a

835b

836

836a

836b

837

837a

837b

838

838a

838b

838c

838d

838e

838f

839

840

840a

840b

841

841a

841b

842

842a

842b

842c

842d

843

844

844a

844b

845

845a

845b

846

846a

846b

847

847a

847b

847b

848

849

849a

849b

850

850a

850b

851

851a

851b

852

852a

852b

853

853a

853b

854

854a

854b

854c

854d

855

855a

855b

856

856a

856b

856c

856d

856e

857

857a

857b

858

858a

858b

859

859a

859b

860

860a

860b

861

861a

861b

862

862a

862b

863

863a

863b

864a

865a

866a

866b

867a

867b

867c

867d

867e

867f

868a

868b

868c

868d

868e

868f

869a

869b

869c

870a

870b

870c

871a

871b

871d

872a

872b

872c

873

873a

873b

874a

874b

875

875a

875b

876a

877a

878a

879a

880a

881a

882a

883a

884a

885a

886a

887a

887b

888a

889

889a

889b

890

891

892

893

894

894a

895

896

897

897a

897b

898

899

900

901

901a

901b

902

902a

902b

903

903a

903b

904

904a

904b

905

906

906a

906b

907

908

908a

908b

909

910

910a

910b

911

911a

911b

911c

911d

912

912a

912b

913

913a

913b

914

914a

914b

915

916

916a

916b

917

918a

919a

919b

919c

919d

919e

919f

920a

920b

920c

920d

921a

921b

921c

921d

921e

921f

922a

923a

924a

925

925a

926

926a

927

927a

928

929

929a

930

931

932

933

933a

934

934a

935

935a

936

937

938

939a

939b

and pharmaceutically acceptable salts thereof.

In some embodiments, provided herein is a compound that is selected from the group consisting of the compounds in Table 1D below:

TABLE 1D Cmpd # Structure 1001

1001a

1001b

1002

1002a

1002b

1003

1003a

1003b

1004

1004a

1004b

1005

1005a

1005b

1006

1006a

1006b

1007

1007a

1007b

1008

1008a

1008b

1009

1009a

1009b

1010

1010a

1010b

1011

1011a

1011b

1012

1012a

1012b

1013

1013a

1013b

1014

1014a

1014b

1015

1015a

1015b

1016

1016a

1016b

1017

1017a

1017b

1018

1018a

1018b

1019

1019a

1019b

1020

1020a

1020b

1021

1021a

1021b

1022

1022a

1022b

1023

1023a

1023b

1024

1024a

1024b

1025

1025a

1025b

1026

1026a

1026b

1026

1026a

1026b

1027

1027a

1027b

1028

1028a

1028b

1028c

1028d

1029

1029a

1029b

1030

1030a

1030b

1030c

1030d

1031

1031a

1031b

1031c

1031d

1032

1032a

1032b

1032c

1032d

1033

1033a

1033b

1033c

1033d

1034

1034a

1034b

1035

1035a

1035b

1036

1036a

1036b

1036c

1036d

1037

1037a

1037b

1038

1038a

1038b

1039

1039a

1039b

1040

1040a

1040b

1041

1041a

1041b

1042

1042a

1042b

1043

1043a

1043b

1044

1044a

1044b

1045

1045a

1045b

1046

1047a

1047b

indicates data missing or illegible when filed

and pharmaceutically acceptable salts thereof.

In some embodiments, provided herein is a compound that is selected from the group consisting of the compounds in Table 1E below:

TABLE 1E Compound # Structure 1100

1101

1102

1103

1104

1105

and pharmaceutically acceptable salts thereof.

In one embodiment, provided herein is a pharmaceutical composition comprising any NLRP3 antagonist species defined here (for example, a compound or example of Tables 1, 1A, 1C, 1D, 1E, 16, 17, 18, 19, B1, B2, B3 and B4), and an anti-TNFα agent disclosed herein. Preferably wherein the anti-TNFα agent is Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab, more preferably wherein the anti-TNFα agent is Adalimumab.

In one embodiment, provided herein is a pharmaceutical combination of a compound of any NLRP3 antagonist species defined here (for example, a compound or example of Tables 1, 1A, 1C, 1D, 1E, 16, 17, 18, 19, B1, B2, B3 and B4), and an anti-TNFα agent Preferably wherein the anti-TNFα agent is Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab, more preferably wherein the anti-TNFα agent is Adalimumab.

Pharmaceutical Compositions and Administration

General

In some embodiments, a chemical entity (e.g., a compound that modulates (e.g., antagonizes) NLRP3, or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination thereof) is administered as a pharmaceutical composition that includes the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

In some embodiments, the chemical entities can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient may be prepared. The contemplated compositions may contain 0.001%400% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22^(nd) Edition (Pharmaceutical Press, London, UK. 2012).

In some embodiments, an NLRP3 antagonist and/or an anti-TNFα agent disclosed herein is administered as a pharmaceutical composition that includes the NLRP3 antagonist and/or anti-TNFα agent and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein. Preferably the pharmaceutical composition that includes an NLRP3 antagonist and an anti-TNFα agent.

Preferably the above pharmaceutical composition embodiments comprise an NLRP3 antagonist disclosed herein. More preferably the above pharmaceutical composition embodiments comprise an NLRP3 antagonist and an anti-TNFα agent disclosed herein.

Routes of Administration and Composition Components

In some embodiments, the chemical entities described herein or a pharmaceutical composition thereof can be administered to subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral).

Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Intratumoral injections are discussed, e.g., in Lammers, et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia. 2006, 10, 788-795.

In certain embodiments, the chemical entities described herein or a pharmaceutical composition thereof are suitable for local, topical administration to the digestive or GI tract, e.g., rectal administration. Rectal compositions include, without limitation, enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, and enemas (e.g., retention enemas).

Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM), lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate.

In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema.

In other embodiments, the compounds described herein or a pharmaceutical composition thereof are suitable for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms.).

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a chemical entity provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG's, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP/NF standard is usually sufficient.

In certain embodiments, solid oral dosage forms can further include one or more components that chemically and/or structurally predispose the composition for delivery of the chemical entity to the stomach or the lower GI; e.g., the ascending colon and/or transverse colon and/or distal colon and/or small bowel. Exemplary formulation techniques are described in, e.g., Filipski, K. J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety.

Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.

Other examples include lower-GI targeting techniques. For targeting various regions in the intestinal tract, several enteric/pH-responsive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymers), and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, Pressure-controlled colon delivery capsule, and Pulsincap.

Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

Topical compositions can include ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and non-sensitizing.

In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

In one embodiment, provided herein is a pharmaceutical composition comprising any NLRP3 antagonist species defined here (for example, a compound or example of Tables 1, 1C, 1D, 1E, B1, B2, B3, and B4), and an anti-TNFα agent disclosed herein. Preferably wherein the anti-TNFα agent is Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab, more preferably wherein the anti-TNFα agent is Adalimumab.

In one embodiment, provided herein is a pharmaceutical combination of a compound of any NLRP3 antagonist species defined here (for example, a compound or example of Tables 1, 1C, 1D, 1E, B1, B2, B3, and B4), and an anti-TNFα agent Preferably wherein the anti-TNFα agent is Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab, more preferably wherein the anti-TNFα agent is Adalimumab.

Enema Formulations

In some embodiments, enema formulations containing the chemical entities described herein are provided in “ready-to-use” form.

In some embodiments, enema formulations containing the chemical entities described herein are provided in one or more kits or packs. In certain embodiments, the kit or pack includes two or more separately contained/packaged components, e.g. two components, which when mixed together, provide the desired formulation (e.g., as a suspension). In certain of these embodiments, the two component system includes a first component and a second component, in which: (i) the first component (e.g., contained in a sachet) includes the chemical entity (as described anywhere herein) and optionally one or more pharmaceutically acceptable excipients (e.g., together formulated as a solid preparation, e.g., together formulated as a wet granulated solid preparation); and (ii) the second component (e.g., contained in a vial or bottle) includes one or more liquids and optionally one or more other pharmaceutically acceptable excipients together forming a liquid carrier. Prior to use (e.g., immediately prior to use), the contents of (i) and (ii) are combined to form the desired enema formulation, e.g., as a suspension. In other embodiments, each of component (i) and (ii) is provided in its own separate kit or pack.

In some embodiments, each of the one or more liquids is water, or a physiologically acceptable solvent, or a mixture of water and one or more physiologically acceptable solvents. Typical such solvents include, without limitation, glycerol, ethylene glycol, propylene glycol, polyethylene glycol and polypropylene glycol. In certain embodiments, each of the one or more liquids is water. In other embodiments, each of the one or more liquids is an oil, e.g. natural and/or synthetic oils that are commonly used in pharmaceutical preparations.

Further pharmaceutical excipients and carriers that may be used in the pharmaceutical products herein described are listed in various handbooks (e.g. D. E. Bugay and W. P. Findlay (Eds) Pharmaceutical excipients (Marcel Dekker, New York, 1999), E-M Hoepfner, A. Reng and P. C. Schmidt (Eds) Fiedler Encyclopedia of Excipients for Pharmaceuticals, Cosmetics and Related Areas (Edition Cantor, Munich, 2002) and H. P. Fielder (Ed) Lexikon der Hilfsstoffe für Pharmazie, Kosmetik and angrenzende Gebiete (Edition Cantor Aulendorf, 1989)).

In some embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selected from thickeners, viscosity enhancing agents, bulking agents, mucoadhesive agents, penetration enhancers, buffers, preservatives, diluents, binders, lubricants, glidants, disintegrants, fillers, solubilizing agents, pH modifying agents, preservatives, stabilizing agents, anti-oxidants, wetting or emulsifying agents, suspending agents, pigments, colorants, isotonic agents, chelating agents, emulsifiers, and diagnostic agents.

In certain embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selected from thickeners, viscosity enhancing agents, mucoadhesive agents, buffers, preservatives, diluents, binders, lubricants, glidants, disintegrants, and fillers.

In certain embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selected from thickeners, viscosity enhancing agents, bulking agents, mucoadhesive agents, buffers, preservatives, and fillers.

In certain embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selected from diluents, binders, lubricants, glidants, and disintegrants.

Examples of thickeners, viscosity enhancing agents, and mucoadhesive agents include without limitation: gums, e.g. xanthan gum, guar gum, locust bean gum, tragacanth gums, karaya gum, ghatti gum, cholla gum, psyllium seed gum and gum arabic; poly(carboxylic acid-containing) based polymers, such as poly (acrylic, maleic, itaconic, citraconic, hydroxyethyl methacrylic or methacrylic) acid which have strong hydrogen-bonding groups, or derivatives thereof such as salts and esters; cellulose derivatives, such as methyl cellulose, ethyl cellulose, methylethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose or cellulose esters or ethers or derivatives or salts thereof; clays such as manomorillonite clays, e.g. Veegun, attapulgite clay; polysaccharides such as dextran, pectin, amylopectin, agar, mannan or polygalactonic acid or starches such as hydroxypropyl starch or carboxymethyl starch; polypeptides such as casein, gluten, gelatin, fibrin glue; chitosan, e.g. lactate or glutamate or carboxymethyl chitin; glycosaminoglycans such as hyaluronic acid; metals or water soluble salts of alginic acid such as sodium alginate or magnesium alginate; schleroglucan; adhesives containing bismuth oxide or aluminium oxide; atherocollagen; polyvinyl polymers such as carboxyvinyl polymers; polyvinylpyrrolidone (povidone); polyvinyl alcohol; polyvinyl acetates, polyvinylmethyl ethers, polyvinyl chlorides, polyvinylidenes, and/or the like; polycarboxylated vinyl polymers such as polyacrylic acid as mentioned above; polysiloxanes; polyethers; polyethylene oxides and glycols; polyalkoxys and polyacrylamides and derivatives and salts thereof. Preferred examples can include cellulose derivatives, such as methyl cellulose, ethyl cellulose, methylethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose or cellulose esters or ethers or derivatives or salts thereof (e.g., methyl cellulose); and polyvinyl polymers such as polyvinylpyrrolidone (povidone).

Examples of preservatives include without limitation: benzalkonium chloride, benzoxonium chloride, benzethonium chloride, cetrimide, sepazonium chloride, cetylpyridinium chloride, domiphen bromide (Bradosol®), thiomersal, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric borate, methylparaben, propylparaben, chlorobutanol, benzyl alcohol, phenyl ethyl alcohol, chlorohexidine, polyhexamethylene biguanide, sodium perborate, imidazolidinyl urea, sorbic acid, Purite®), Polyquart®), and sodium perborate tetrahydrate and the like.

In certain embodiments, the preservative is a paraben, or a pharmaceutically acceptable salt thereof. In some embodiments, the paraben is an alkyl substituted 4-hydroxybenzoate, or a pharmaceutically acceptable salt or ester thereof. In certain embodiments, the alkyl is a C1-C4 alkyl. In certain embodiments, the preservative is methyl 4-hydroxybenzoate (methylparaben), or a pharmaceutically acceptable salt or ester thereof, propyl 4-hydroxybenzoate (propylparaben), or a pharmaceutically acceptable salt or ester thereof, or a combination thereof.

Examples of buffers include without limitation: phosphate buffer system (sodium dihydrogen phospahate dehydrate, disodium phosphate dodecahydrate, bibasic sodium phosphate, anhydrous monobasic sodium phosphate), bicarbonate buffer system, and bisulfate buffer system.

Examples of disintegrants include, without limitation: carmellose calcium, low substituted hydroxypropyl cellulose (L-HPC), carmellose, croscarmellose sodium, partially pregelatinized starch, dry starch, carboxymethyl starch sodium, crospovidone, polysorbate 80 (polyoxyethylenesorbitan oleate), starch, sodium starch glycolate, hydroxypropyl cellulose pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross-linked PVP (Polyplasdone XL from GAF Chemical Corp). In certain embodiments, the disintegrant is crospovidone.

Examples of glidants and lubricants (aggregation inhibitors) include without limitation: talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, aqueous silicon dioxide, synthetic magnesium silicate, fine granulated silicon oxide, starch, sodium laurylsulfate, boric acid, magnesium oxide, waxes, hydrogenated oil, polyethylene glycol, sodium benzoate, stearic acid glycerol behenate, polyethylene glycol, and mineral oil. In certain embodiments, the glidant/lubricant is magnesium stearate, talc, and/or colloidal silica; e.g., magnesium stearate and/or talc.

Examples of diluents, also referred to as “fillers” or “bulking agents” include without limitation: dicalcium phosphate dihydrate, calcium sulfate, lactose (e.g., lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar. In certain embodiments, the diluent is lactose (e.g., lactose monohydrate).

Examples of binders include without limitation: starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia tragacanth, sodium alginate cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone (povidone). In certain embodiments, the binder is polyvinylpyrrolidone (povidone).

In some embodiments, enema formulations containing the chemical entities described herein include water and one or more (e.g., all) of the following excipients:

-   -   One or more (e.g., one, two, or three) thickeners, viscosity         enhancing agents, binders, and/or mucoadhesive agents (e.g.,         cellulose or cellulose esters or ethers or derivatives or salts         thereof (e.g., methyl cellulose); and polyvinyl polymers such as         polyvinylpyrrolidone (povidone);     -   One or more (e.g., one or two; e.g., two) preservatives, such as         a paraben, e.g., methyl 4-hydroxybenzoate (methylparaben), or a         pharmaceutically acceptable salt or ester thereof, propyl         4-hydroxybenzoate (propylparaben), or a pharmaceutically         acceptable salt or ester thereof, or a combination thereof;     -   One or more (e.g., one or two; e.g., two) buffers, such as         phosphate buffer system (e.g., sodium dihydrogen phospahate         dehydrate, disodium phosphate dodecahydrate);     -   One or more (e.g., one or two, e.g., two) glidants and/or         lubricants, such as magnesium stearate and/or talc;     -   One or more (e.g., one or two; e.g., one) disintegrants, such as         crospovidone; and     -   One or more (e.g., one or two; e.g., one) diluents, such as         lactose (e.g., lactose monohydrate).

In certain of these embodiments, the chemical entity is a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof.

In certain embodiments, enema formulations containing the chemical entities described herein include water, methyl cellulose, povidone, methylparaben, propylparaben, sodium dihydrogen phospahate dehydrate, disodium phosphate dodecahydrate, crospovidone, lactose monohydrate, magnesium stearate, and talc. In certain of these embodiments, the chemical entity is a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof.

In certain embodiments, enema formulations containing the chemical entities described herein are provided in one or more kits or packs. In certain embodiments, the kit or pack includes two separately contained/packaged components, which when mixed together, provide the desired formulation (e.g., as a suspension). In certain of these embodiments, the two component system includes a first component and a second component, in which: (i) the first component (e.g., contained in a sachet) includes the chemical entity (as described anywhere herein) and one or more pharmaceutically acceptable excipients (e.g., together formulated as a solid preparation, e.g., together formulated as a wet granulated solid preparation); and (ii) the second component (e.g., contained in a vial or bottle) includes one or more liquids and one or more one or more other pharmaceutically acceptable excipients together forming a liquid carrier. In other embodiments, each of component (i) and (ii) is provided in its own separate kit or pack.

In certain of these embodiments, component (i) includes the chemical entitiy (e.g., a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof; e.g., a compound of Formula AA) and one or more (e.g., all) of the following excipients:

-   -   (a) One or more (e.g., one) binders (e.g., a polyvinyl polymer,         such as polyvinylpyrrolidone (povidone);     -   (b) One or more (e.g., one or two, e.g., two) glidants and/or         lubricants, such as magnesium stearate and/or talc;     -   (c) One or more (e.g., one or two; e.g., one) disintegrants,         such as crospovidone; and     -   (d) One or more (e.g., one or two; e.g., one) diluents, such as         lactose (e.g., lactose monohydrate).

In certain embodiments, component (i) includes from about 40 weight percent to about 80 weight percent (e.g., from about 50 weight percent to about 70 weight percent, from about 55 weight percent to about 70 weight percent; from about 60 weight percent to about 65 weight percent; e.g., about 62.1 weight percent) of the chemical entity (e.g., a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof).

In certain embodiments, component (i) includes from about 0.5 weight percent to about 5 weight percent (e.g., from about 1.5 weight percent to about 4.5 weight percent, from about 2 weight percent to about 3.5 weight percent; e.g., about 2.76 weight percent) of the binder (e.g., povidone).

In certain embodiments, component (i) includes from about 0.5 weight percent to about 5 weight percent (e.g., from about 0.5 weight percent to about 3 weight percent, from about 1 weight percent to about 3 weight percent; about 2 weight percent e.g., about 1.9 weight percent) of the disintegrant (e.g., crospovidone).

In certain embodiments, component (i) includes from about 10 weight percent to about 50 weight percent (e.g., from about 20 weight percent to about 40 weight percent, from about 25 weight percent to about 35 weight percent; e.g., about 31.03 weight percent) of the diluent (e.g., lactose, e.g., lactose monohydrate).

In certain embodiments, component (i) includes from about 0.05 weight percent to about 5 weight percent (e.g., from about 0.05 weight percent to about 3 weight percent) of the glidants and/or lubricants.

In certain embodiments (e.g., when component (i) includes one or more lubricants, such as magnesium stearate), component (i) includes from about 0.05 weight percent to about 1 weight percent (e.g., from about 0.05 weight percent to about 1 weight percent; from about 0.1 weight percent to about 1 weight percent; from about 0.1 weight percent to about 0.5 weight percent; e.g., about 0.27 weight percent) of the lubricant (e.g., magnesium stearate).

In certain embodiments (when component (i) includes one or more lubricants, such as talc), component (i) includes from about 0.5 weight percent to about 5 weight percent (e.g., from about 0.5 weight percent to about 3 weight percent, from about 1 weight percent to about 3 weight percent; from about 1.5 weight percent to about 2.5 weight percent; from about 1.8 weight percent to about 2.2 weight percent; about 1.93 weight percent) of the lubricant (e.g., talc).

In certain of these embodiments, each of (a), (b), (c), and (d) above is present.

In certain embodiments, component (i) includes the ingredients and amounts as shown in Table A.

TABLE A Ingredient Weight Percent A compound of Formula 40 weight percent to about 80 weight AA percent (e.g., from about 50 weight percent to about 70 weight percent, from about 55 weight percent to about 70 weight percent; from about 60 weight percent to about 65 weight percent; e.g., about 62.1 weight percent) Crospovidone (Kollidon 0.5 weight percent to about 5 weight CL) percent (e.g., from about 0.5 weight percent to about 3 weight percent, from about 1 weight percent to about 3 weight percent; about 1.93 weight percent lactose monohydrate about 10 weight percent to about 50 weight (Pharmatose 200M) percent (e.g., from about 20 weight percent to about 40 weight percent, from about 25 weight percent to about 35 weight percent; e.g., about 31.03 weight percent Povidone (Kollidon K30) about 0.5 weight percent to about 5 weight percent (e.g., from about 1.5 weight percent to about 4.5 weight percent, from about 2 weight percent to about 3.5 weight percent; e.g., about 2.76 weight percent talc 0.5 weight percent to about 5 weight percent (e.g., from about 0.5 weight percent to about 3 weight percent, from about 1 weight percent to about 3 weight percent; from about 1.5 weight percent to about 2.5 weight percent; from about 1.8 weight percent to about 2.2 weight percent; e.g., about 1.93 weight percent Magnesium stearate about 0.05 weight percent to about 1 weight percent (e.g., from about 0.05 weight percent to about 1 weight percent; from about 0.1 weight percent to about 1 weight percent; from about 0.1 weight percent to about 0.5 weight percent; e.g., about 0.27 weight percent

In certain embodiments, component (1) includes the ingredients and amounts as shown in Table B.

TABLE B Ingredient Weight Percent A compound of Formula About 62.1 weight percent) AA Crospovidone (Kollidon About 1.93 weight percent CL) lactose monohydrate About 31.03 weight percent (Pharmatose 200M) Povidone (Kollidon K30) About 2.76 weight percent talc About 1.93 weight percent Magnesium stearate About 0.27 weight percent

In certain embodiments, component (1) is formulated as a wet granulated solid preparation. In certain of these embodiments an internal phase of ingredients (the chemical entity, disintegrant, and diluent) are combined and mixed in a high-shear granulator. A binder (e.g., povidone) is dissolved in water to form a granulating solution. This solution is added to the Inner Phase mixture resulting in the development of granules. While not wishing to be bound by theory, granule development is believed to be facilitated by the interaction of the polymeric binder with the materials of the internal phase. Once the granulation is formed and dried, an external phase (e.g., one or more lubricants—not an intrinsic component of the dried granulation), is added to the dry granulation. It is believed that lubrication of the granulation is important to the flowability of the granulation, in particular for packaging.

In certain of the foregoing embodiments, component (ii) includes water and one or more (e.g., all) of the following excipients:

-   -   (a′) One or more (e.g., one, two; e.g., two) thickeners,         viscosity enhancing agents, binders, and/or mucoadhesive agents         (e.g., cellulose or cellulose esters or ethers or derivatives or         salts thereof (e.g., methyl cellulose); and polyvinyl polymers         such as polyvinylpyrrolidone (povidone);     -   (b′) One or more (e.g., one or two; e.g., two) preservatives,         such as a paraben, e.g., methyl 4-hydroxybenzoate         (methylparaben), or a pharmaceutically acceptable salt or ester         thereof, propyl 4-hydroxybenzoate (propylparaben), or a         pharmaceutically acceptable salt or ester thereof, or a         combination thereof; and     -   (c′) One or more (e.g., one or two; e.g., two) buffers, such as         phosphate buffer system (e.g., sodium dihydrogen phospahate         dihydrate, disodium phosphate dodecahydrate);

In certain of the foregoing embodiments, component (ii) includes water and one or more (e.g., all) of the following excipients:

-   -   (a″) a first thickener, viscosity enhancing agent, binder,         and/or mucoadhesive agent (e.g., a cellulose or cellulose ester         or ether or derivative or salt thereof (e.g., methyl         cellulose));     -   (a″′) a second thickener, viscosity enhancing agent, binder,         and/or mucoadhesive agent (e.g., a polyvinyl polymer, such as         polyvinylpyrrolidone (povidone));     -   (b″) a first preservative, such as a paraben, e.g., propyl         4-hydroxybenzoate (propylparaben), or a pharmaceutically         acceptable salt or ester thereof;     -   (b″) a second preservative, such as a paraben, e.g., methyl         4-hydroxybenzoate (methylparaben), or a pharmaceutically         acceptable salt or ester thereof,     -   (c″) a first buffer, such as phosphate buffer system (e.g.,         disodium phosphate dodecahydrate);     -   (c′″) a second buffer, such as phosphate buffer system (e.g.,         sodium dihydrogen phospahate dehydrate),

In certain embodiments, component (ii) includes from about 0.05 weight percent to about 5 weight percent (e.g., from about 0.05 weight percent to about 3 weight percent, from about 0.1 weight percent to about 3 weight percent; e.g., about 1.4 weight percent) of (a″).

In certain embodiments, component (ii) includes from about 0.05 weight percent to about 5 weight percent (e.g., from about 0.05 weight percent to about 3 weight percent, from about 0.1 weight percent to about 2 weight percent; e.g., about 1.0 weight percent) of (a″′).

In certain embodiments, component (ii) includes from about 0.005 weight percent to about 0.1 weight percent (e.g., from about 0.005 weight percent to about 0.05 weight percent; e.g., about 0.02 weight percent) of (b″).

In certain embodiments, component (ii) includes from about 0.05 weight percent to about 1 weight percent (e.g., from about 0.05 weight percent to about 0.5 weight percent; e.g., about 0.20 weight percent) of (b″′).

In certain embodiments, component (ii) includes from about 0.05 weight percent to about 1 weight percent (e.g., from about 0.05 weight percent to about 0.5 weight percent; e.g., about 0.15 weight percent) of (c″).

In certain embodiments, component (ii) includes from about 0.005 weight percent to about 0.5 weight percent (e.g., from about 0.005 weight percent to about 0.3 weight percent; e.g., about 0.15 weight percent) of (c′″).

In certain of these embodiments, each of (a″)-(c′) is present.

In certain embodiments, component (ii) includes water (up to 100%) and the ingredients and amounts as shown in Table C.

TABLE C Ingredient Weight Percent methyl cellulose (Methocel 0.05 weight percent to about 5 weight A15C premium) percent (e.g., from about 0.05 weight percent to about 3 weight percent, from about 0.1 weight percent to about 3 weight percent; e.g., about 1.4 weight percent Povidone (Kollidon K30) 0.05 weight percent to about 5 weight percent (e.g., from about 0.05 weight percent to about 3 weight percent, from about 0.1 weight percent to about 2 weight percent; e.g., about 1.0 weight percent propyl 4-hydroxybenzoate about 0.005 weight percent to about 0.1 weight percent (e.g., from about 0.005 weight percent to about 0.05 weight percent; e.g., about 0.02 weight percent) methyl 4-hydroxybenzoate about 0.05 weight percent to about 1 weight percent (e.g., from about 0.05 weight percent to about 0.5 weight percent; e.g., about 0.20 weight percent) disodium phosphate about 0.05 weight percent to about 1 dodecahydrate weight percent (e.g., from about 0.05 weight percent to about 0.5 weight percent; e.g., about 0.15 weight percent) sodium dihydrogen about 0.005 weight percent to about 0.5 phospahate dihydrate weight percent (e.g., from about 0.005 weight percent to about 0.3 weight percent; e.g., about 0.15 weight percent)

In certain embodiments, component (ii) includes water (up to 100%) and the ingredients and amounts as shown in Table D.

TABLE D Ingredient Weight Percent methyl cellulose (Methocel about 1.4 weight percent A15C premium) Povidone (Kollidon K30) about 1.0 weight percent propyl 4-hydroxybenzoate about 0.02 weight percent methyl 4-hydroxybenzoate about 0.20 weight percent disodium phosphate about 0.15 weight percent dodecahydrate sodium dihydrogen about 0.15 weight percent phospahate dihydrate

Ready-to-use” enemas are generally be provided in a “single-use” sealed disposable container of plastic or glass. Those formed of a polymeric material preferably have sufficient flexibility for ease of use by an unassisted patient. Typical plastic containers can be made of polyethylene. These containers may comprise a tip for direct introduction into the rectum. Such containers may also comprise a tube between the container and the tip. The tip is preferably provided with a protective shield which is removed before use. Optionally the tip has a lubricant to improve patient compliance.

In some embodiments, the enema formulation (e.g., suspension) is poured into a bottle for delivery after it has been prepared in a separate container. In certain embodiments, the bottle is a plastic bottle (e.g., flexible to allow for delivery by squeezing the bottle), which can be a polyethylene bottle (e.g., white in color). In some embodiments, the bottle is a single chamber bottle, which contains the suspension or solution. In other embodiments, the bottle is a multichamber bottle, where each chamber contains a separate mixture or solution. In still other embodiments, the bottle can further include a tip or rectal cannula for direct introduction into the rectum.

Dosages

The dosages may be varied depending on the requirement of the patient, the severity of the condition being treating and the particular compound being employed. Determination of the proper dosage for a particular situation can be determined by one skilled in the medical arts. The total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.

In some embodiments, the compounds described herein are administered at a dosage of from about 0.001 mg/Kg to about 500 mg/Kg (e.g., from about 0.001 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 150 mg/Kg; from about 0.01 mg/Kg to about 100 mg/Kg; from about 0.01 mg/Kg to about 50 mg/Kg; from about 0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kg to about 5 mg/Kg; from about 0.01 mg/Kg to about 1 mg/Kg; from about 0.01 mg/Kg to about 0.5 mg/Kg; from about 0.01 mg/Kg to about 0.1 mg/Kg; from about 0. 1 mg/Kg to about 200 mg/Kg; from about 0. 1 mg/Kg to about 150 mg/Kg; from about 0. 1 mg/Kg to about 100 mg/Kg; from about 0.1 mg/Kg to about 50 mg/Kg; from about 0. 1 mg/Kg to about 10 mg/Kg; from about 0. 1 mg/Kg to about 5 mg/Kg; from about 0. 1 mg/Kg to about 1 mg/Kg; from about 0. 1 mg/Kg to about 0.5 mg/Kg).

In some embodiments, enema formulations include from about 0.5 mg to about 2500 mg (e.g., from about 0.5 mg to about 2000 mg, from about 0.5 mg to about 1000 mg, from about 0.5 mg to about 750 mg, from about 0.5 mg to about 600 mg, from about 0.5 mg to about 500 mg, from about 0.5 mg to about 400 mg, from about 0.5 mg to about 300 mg, from about 0.5 mg to about 200 mg; e.g., from about 5 mg to about 2500 mg, from about 5 mg to about 2000 mg, from about 5 mg to about 1000 mg; from about 5 mg to about 750 mg; from about 5 mg to about 600 mg; from about 5 mg to about 500 mg; from about 5 mg to about 400 mg; from about 5 mg to about 300 mg; from about 5 mg to about 200 mg; e.g., from about 50 mg to about 2000 mg, from about 50 mg to about 1000 mg, from about 50 mg to about 750 mg, from about 50 mg to about 600 mg, from about 50 mg to about 500 mg, from about 50 mg to about 400 mg, from about 50 mg to about 300 mg, from about 50 mg to about 200 mg; e.g., from about 100 mg to about 2500 mg, from about 100 mg to about 2000 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 750 mg, from about 100 mg to about 700 mg, from about 100 mg to about 600 mg, from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, from about 100 mg to about 200 mg; e.g., from about 150 mg to about 2500 mg, from about 150 mg to about 2000 mg, from about 150 mg to about 1000 mg, from about 150 mg to about 750 mg, from about 150 mg to about 700 mg, from about 150 mg to about 600 mg, from about 150 mg to about 500 mg, from about 150 mg to about 400 mg, from about 150 mg to about 300 mg, from about 150 mg to about 200 mg; e.g., from about 150 mg to about 500 mg; e.g., from about 300 mg to about 2500 mg, from about 300 mg to about 2000 mg, from about 300 mg to about 1000 mg, from about 300 mg to about 750 mg, from about 300 mg to about 700 mg, from about 300 mg to about 600 mg; e.g., from about 400 mg to about 2500 mg, from about 400 mg to about 2000 mg, from about 400 mg to about 1000 mg, from about 400 mg to about 750 mg, from about 400 mg to about 700 mg, from about 400 mg to about 600 from about 400 mg to about 500 mg; e.g., 150 mg or 450 mg) of the chemical entity in from about 1 mL to about 3000 mL (e.g., from about 1 mL to about 2000 mL, from about 1 mL to about 1000 mL, from about 1 mL to about 500 mL, from about 1 mL to about 250 mL, from about 1 mL to about 100 mL, from about 10 mL to about 1000 mL, from about 10 mL to about 500 mL, from about 10 mL to about 250 mL, from about 10 mL to about 100 mL, from about 30 mL to about 90 mL, from about 40 mL to about 80 mL; from about 50 mL to about 70 mL; e.g., about 1 mL, about 5 mL, about 10 mL, about 15 mL, about 20 mL, about 25 mL, about 30 mL, about 35 mL, about 40 mL, about 45 mL, about 50 mL, about 55 mL, about 60 mL, about 65 mL, about 70 mL, about 75 mL, about 100 mL, about 250 mL, or about 500 mL, or about 1000 mL, or about 2000 mL, or about 3000 mL; e.g., 60 mL) of liquid carrier.

In certain embodiments, enema formulations include from about 50 mg to about 250 mg (e.g., from about 100 mg to about 200; e.g., about 150 mg) of the chemical entity in from about 10 mL to about 100 mL (e.g., from about 20 mL to about 100 mL, from about 30 mL to about 90 mL, from about 40 mL to about 80 mL; from about 50 mL to about 70 mL) of liquid carrier. In certain embodiments, enema formulations include about 150 mg of the chemical entity in about 60 mL of the liquid carrier. In certain of these embodiments, the chemical entity is a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof. For example, enema formulations can include about 150 mg of a compound of Formula AA in about 60 mL of the liquid carrier.

In certain embodiments, enema formulations include from about 350 mg to about 550 mg (e.g., from about 400 mg to about 500; e.g., about 450 mg) of the chemical entity in from about 10 mL to about 100 mL (e.g., from about 20 mL to about 100 mL, from about 30 mL to about 90 mL, from about 40 mL to about 80 mL; from about 50 mL to about 70 mL) of liquid carrier. In certain embodiments, enema formulations include about 450 mg of the chemical entity in about 60 mL of the liquid carrier. In certain of these embodiments, the chemical entity is a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof. For example, enema formulations can include about 450 mg of a compound of Formula AA in about 60 mL of the liquid carrier.

In some embodiments, enema formulations include from about from about 0.01 mg/mL to about 50 mg/mL (e.g., from about 0.01 mg/mL to about 25 mg/mL; from about 0.01 mg/mL to about 10 mg/mL; from about 0.01 mg/mL to about 5 mg/mL; from about 0.1 mg/mL to about 50 mg/mL; from about 0.01 mg/mL to about 25 mg/mL; from about 0.1 mg/mL to about 10 mg/mL; from about 0.1 mg/mL to about 5 mg/mL; from about 1 mg/mL to about 10 mg/mL; from about 1 mg/mL to about 5 mg/mL; from about 5 mg/mL to about 10 mg/mL; e.g., about 2.5 mg/mL or about 7.5 mg/mL) of the chemical entity in liquid carrier. In certain of these embodiments, the chemical entity is a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof. For example, enema formulations can include about 2.5 mg/mL or about 7.5 mg/mL of a compound of Formula AA in liquid carrier.

Regimens

The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).

In some embodiments, the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In an embodiment, a therapeutic compound is administered to an individual for a period of time followed by a separate period of time. In another embodiment, a therapeutic compound is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the therapeutic compound is started and then a fourth period following the third period where administration is stopped. In an aspect of this embodiment, the period of administration of a therapeutic compound followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

Methods of Treatment

In some embodiments, methods for treating a subject having condition, disease or disorder in which a decrease or increase in NLRP3 activity (e.g., an increase, e.g., NLRP3 signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder are provided, comprising administering to a subject an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).

Indications

In some embodiments, the condition, disease or disorder is selected from: inappropriate host responses to infectious diseases where active infection exists at any body site, such as septic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome; acute or chronic inflammation due to antigen, antibody and/or complement deposition; inflammatory conditions including arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury and vasculitis, immune-based diseases such as acute and delayed hypersensitivity, graft rejection, and graft-versus-host disease; auto-immune diseases including Type 1 diabetes mellitus and multiple sclerosis. For example, the condition, disease or disorder may be an inflammatory disorder such as rheumatoid arthritis, osteoarthritis, septic shock, COPD and periodontal disease.

In some embodiments, the condition, disease or disorder is an autoimmune diseases. Non-limiting examples include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel diseases (IBDs) comprising Crohn disease (CD) and ulcerative colitis (UC), which are chronic inflammatory conditions with polygenic susceptibility. In certain embodiments, the condition is an inflammatory bowel disease. In certain embodiments, the condition is Crohn's disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by treatment with adoptive cell therapy, colitis associated by one or more alloimmune diseases (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis. In certain of these embodiments, the condition is alloimmune disease (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), celiac disease, irritable bowel syndrome, rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (e.g., oral mucositis, esophageal mucositis or intestinal mucositis).

In some embodiments, the condition, disease or disorder is selected from major adverse cardiovascular events such as carbiovascular death, non-fatal myocardial infarction and non-fatal stroke in patients with a prior hear attack and inflammatory atherosclerosis (see for example, NCT01327846).

In some embodiments, the condition, disease or disorder is selected from metabolic disorders such as type 2 diabetes, atherosclerosis, obesity and gout, as well as diseases of the central nervous system, such as Alzheimer's disease and multiple sclerosis and Amyotrophic Lateral Sclerosis and Parkinson disease, lung disease, such as asthma and COPD and pulmonary idiopathic fibrosis, liver disease, such as NASH syndrome, viral hepatitis and cirrhosis, pancreatic disease, such as acute and chronic pancreatitis, kidney disease, such as acute and chronic kidney injury, intestinal disease such as Crohn's disease and Ulcerative Colitis, skin disease such as psoriasis, musculoskeletal disease such as scleroderma, vessel disorders, such as giant cell arteritis, disorders of the bones, such as Osteoarthritis , osteoporosis and osteopetrosis disorders eye disease, such as glaucoma and macular degeneration, diseased caused by viral infection such as HIV and AIDS, autoimmune disease such as Rheumatoid Arthritis, Systemic Lupus Erythematosus, Autoimmune Thyroiditis, Addison's disease, pernicious anemia, cancer and aging.

In some embodiments, the condition, disease or disorder is a cardiovascular indication. In some embodiments, the condition, disease or disorder is myocardial infraction. In some embodiments, the condition, disease or disorder is stroke.

In some embodiments, the condition, disease or disorder is obesity.

In some embodiments, the condition, disease or disorder is Type 2 Diabetes.

In some embodiments, the condition, disease or disorder is NASH.

In some embodiments, the condition, disease or disorder is Alzheimer's disease.

In some embodiments, the condition, disease or disorder is gout.

In some embodiments, the condition, disease or disorder is SLE.

In some embodiments, the condition, disease or disorder is rheumatoid arthritis.

In some embodiments, the condition, disease or disorder is IBD.

In some embodiments, the condition, disease or disorder is multiple sclerosis.

In some embodiments, the condition, disease or disorder is COPD.

In some embodiments, the condition, disease or disorder is asthma.

In some embodiments, the condition, disease or disorder is scleroderma.

In some embodiments, the condition, disease or disorder is pulmonary fibrosis.

In some embodiments, the condition, disease or disorder is age related macular degeneration (AMD).

In some embodiments, the condition, disease or disorder is cystic fibrosis.

In some embodiments, the condition, disease or disorder is Muckle Wells syndrome.

In some embodiments, the condition, disease or disorder is familial cold autoinflammatory syndrome (FCAS).

In some embodiments, the condition, disease or disorder is chronic neurologic cutaneous and articular syndrome.

In some embodiments, the condition, disease or disorder is selected from: myelodysplastic syndromes (MDS); non-small cell lung cancer, such as non-small cell lung cancer in patients carrying mutation or overexpression of NLRP3; acute lymphoblastic leukemia (ALL), such as ALL in patients resistant to glucocorticoids treatment; Langerhan's cell histiocytosis (LCH); multiple myeloma; promyelocytic leukemia; acute myeloid leukemia (AML) chronic myeloid leukemia (CML); gastric cancer; and lung cancer metastasis.

In some embodiments, the condition, disease or disorder is selected from: myelodysplastic syndromes (MDS); non-small cell lung cancer, such as non-small cell lung cancer in patients carrying mutation or overexpression of NLRP3; acute lymphoblastic leukemia (ALL), such as ALL in patients resistant to glucocorticoids treatment; Langerhan's cell histiocytosis (LCH); multiple myeloma; promyelocytic leukemia; gastric cancer; and lung cancer metastasis.

In some embodiments, the indication is MDS.

In some embodiments, the indication is non-small lung cancer in patients carrying mutation or overexpression of NLRP3.

In some embodiments, the indication is ALL in patients resistant to glucocorticoids treatment.

In some embodiments, the indication is LCH.

In some embodiments, the indication is multiple myeloma.

In some embodiments, the indication is promyelocytic leukemia.

In some embodiments, the indication is gastric cancer.

In some embodiments, the indication is lung cancer metastasis.

Combination Therapy

This disclosure contemplates both monotherapy regimens as well as combination therapy regimens.

In some embodiments, the methods described herein can further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and/or one or more therapeutic regimens) in combination with administration of the compounds described herein.

In certain embodiments, the second therapeutic agent or regimen is administered to the subject prior to contacting with or administering the chemical entity (e.g., about one hour prior, or about 6 hours prior, or about 12 hours prior, or about 24 hours prior, or about 48 hours prior, or about 1 week prior, or about 1 month prior).

In other embodiments, the second therapeutic agent or regimen is administered to the subject at about the same time as contacting with or administering the chemical entity. By way of example, the second therapeutic agent or regimen and the chemical entity are provided to the subject simultaneously in the same dosage form. As another example, the second therapeutic agent or regimen and the chemical entity are provided to the subject concurrently in separate dosage forms.

In still other embodiments, the second therapeutic agent or regimen is administered to the subject after contacting with or administering the chemical entity (e.g., about one hour after, or about 6 hours after, or about 12 hours after, or about 24 hours after, or about 48 hours after, or about 1 week after, or about 1 month after).

Patient Selection

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related to NLRP3 polymorphism.

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related to NLRP3 where polymorphism is a gain of function

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related to NLRP3 polymorphism found in CAPS syndromes.

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related NLRP3 polymorphism where the polymorphism is VAR_014104 (R262W)

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related NLRP3 polymorphism where the polymorphism is a natural variant reported in http://www.uniprot.org/uniprot/Q96P20.

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related to point mutation of NLRP3 signaling.

Anti-TNFα Agents

The term “anti-TNFα agent” refers to an agent which directly or indirectly blocks, down-regulates, impairs, inhibits, impairs, or reduces TNFα activity and/or expression. In some embodiments, an anti-TNFα agent is an antibody or an antigen-binding fragment thereof, a fusion protein, a soluble TNFα receptor (a soluble tumor necrosis factor receptor superfamily member 1A (TNFR1) or a soluble tumor necrosis factor receptor superfamily 1B (TNFR2)), an inhibitory nucleic acid, or a small molecule TNFα antagonist. In some embodiments, the inhibitory nucleic acid is a ribozyme, small hairpin RNA, a small interfering RNA, an antisense nucleic acid, or an aptamer.

Exemplary anti-TNFα agents that directly block, down-regulate, impair, inhibit, or reduce TNFα activity and/or expression can, e.g., inhibit or decrease the expression level of TNFα or a receptor of TNFα (TNFR1 or TNFR2) in a cell (e.g., a cell obtained from a subject, a mammalian cell), or inhibit or reduce binding of TNFα to its receptor (TNFR1 and/or TNFR2) and/or. Non-limiting examples of anti-TNFα agents that directly block, down-regulate, impair, inhibit, or reduce TNFα activity and/or expression include an antibody or fragment thereof, a fusion protein, a soluble TNFα receptor (e.g., a soluble TNFR1 or soluble TNFR2), inhibitory nucleic acids (e.g., any of the examples of inhibitory nucleic acids described herein), and a small molecule TNFα antagonist.

Exemplary anti-TNFα agents that can indirectly block, down-regulate, impair, inhibitreduce TNFα activity and/or expression can, e.g., inhibit or decrease the level of downstream signaling of a TNFα receptor (e.g., TNFR1 or TNFR2) in a mammalian cell (e.g., decrease the level and/or activity of one or more of the following signaling proteins: AP-1, mitogen-activated protein kinase kinase kinase 5 (ASK1), inhibitor of nuclear factor kappa B (IKK), mitogen-activated protein kinase 8 (JNK), mitogen-activated protein kinase (MAPK), MEKK 1/4, MEKK 4/7, MEKK 3/6, nuclear factor kappa B (NF-κB), mitogen-activated protein kinase kinase kinase 14 (NIK), receptor interacting serine/threonine kinase 1 (RIP), TNFRSF1A associated via death domain (TRADD), and TNF receptor associated factor 2 (TRAF2), in a cell), and/or decrease the level of TNFα-induced gene expression in a mammalian cell (e.g., decrease the transcription of genes regulated by, e.g., one or more transcription factors selected from the group of activating transcription factor 2 (ATF2), c-Jun, and NF-κB). A description of downstream signaling of a TNFα receptor is provided in Wajant et al., Cell Death Differentiation 10:45-65, 2003 (incorporated herein by reference). For example, such indirect anti-TNFα agents can be an inhibitory nucleic acid that targets (decreases the expression) a signaling component downstream of a TNFα-induced gene (e.g., any TNFα-induced gene known in the art), a TNFα receptor (e.g., any one or more of the signaling components downstream of a TNFα receptor described herein or known in the art), or a transcription factor selected from the group of NF-κB, c-Jun, and ATF2.

In other examples, such indirect anti-TNFα agents can be a small molecule inhibitor of a protein encoded by a TNFα-induced gene (e.g., any protein encoded by a TNFα-induced gene known in the art), a small molecule inhibitor of a signaling component downstream of a TNFα receptor (e.g., any of the signaling components downstream of a TNFα receptor described herein or known in the art), and a small molecule inhibitor of a transcription factor selected from the group of ATF2, c-Jun, and NF-κB.

In other embodiments, anti-TNFα agents that can indirectly block, down-regulate, impair, or reduce one or more components in a cell (e.g., a cell obtained from a subject, a mammalian cell) that are involved in the signaling pathway that results in TNFα mRNA transcription, TNFα mRNA stabilization, and TNFα mRNA translation (e.g., one or more components selected from the group of CD14, c-Jun, ERK1/2, IKK, IκB, interleukin 1 receptor associated kinase 1 (IRAK), JNK, lipopolysaccharide binding protein (LBP), MEK1/2, MEK3/6, MEK4/7, MK2, MyD88, NF-κB, NIK, PKR, p38, AKT serine/threonine kinase 1 (rac), raf kinase (raf), ras, TRAF6, TTP). For example, such indirect anti-TNFα agents can be an inhibitory nucleic acid that targets (decreases the expression) of a component in a mammalian cell that is involved in the signaling pathway that results in TNFα mRNA transcription, TNFα mRNA stabilization, and TNFα mRNA translation (e.g., a component selected from the group of CD14, c-Jun, ERK1/2, IKK, IκB, IRAK, JNK, LBP, MEK1/2, MEK3/6, MEK4/7, MK2, MyD88, NF-κB, NIK, IRAK, lipopolysaccharide binding protein (LBP), PKR, p38, rac, raf, ras, TRAF6, TTP). In other examples, an indirect anti-TNFα agents is a small molecule inhibitor of a component in a mammalian cell that is involved in the signaling pathway that results in TNFα mRNA transcription, TNFα mRNA stabilization, and TNFα mRNA translation (e.g., a component selected from the group of CD14, c-Jun, ERK1/2, IKK, IκB, IRAK, JNK, lipopolysaccharide binding protein (LBP), MEK1/2, MEK3/6, MEK4/7, MK2, MyD88, NF-κB, NIK, IRAK, lipopolysaccharide binding protein (LBP), PKR, p38, rac, raf, ras, TRAF6, TTP).

Antibodies

In some embodiments, the anti-TNFα agent is an antibody or an antigen-binding fragment thereof (e.g., a Fab or a scFv). In some embodiments, an antibody or antigen-binding fragment of an antibody described herein can bind specifically to TNFα. In some embodiments, an antibody or antigen-binding fragment described herein binds specifically to any one of TNFα, TNFR1, or TNFR2. In some embodiments, an antibody or antigen-binding fragment of an antibody described herein can bind specifically to a TNFα receptor (TNFR1 or TNFR2).

In some embodiments, the antibody can be a humanized antibody, a chimeric antibody, a multivalent antibody, or a fragment thereof. In some embodiments, an antibody can be a scFv-Fc, a VHH domain, a VNAR domain, a (scFv)2, a minibody, or a BiTE.

In some embodiments, an antibody can be a crossmab, a diabody, a scDiabody, a scDiabody-CH3, a Diabody-CH3, a DutaMab, a DT-IgG, a diabody-Fc, a scDiabody-HAS, a charge pair antibody, a Fab-arm exchange antibody, a SEEDbody, a Triomab, a LUZ-Y, a Fcab, a kλ-body, an orthogonal Fab, a DVD-IgG, an IgG(H)-scFv, a scFv-(H)IgG, an IgG(L)-scFv, a scFv-(L)-IgG, an IgG (L,H)-Fc, an IgG(H)-V, a V(H)-IgG, an IgG(L)-V, a V(L)-IgG, an KIH IgG-scFab, a 2scFv-IgG, an IgG-2scFv, a scFv4-Ig, a Zybody, a DVI-IgG, a nanobody, a nanobody-HSA, a DVD-Ig, a dual-affinity re-targeting antibody (DART), a triomab, a kih IgG with a common LC, an ortho-Fab IgG, a 2-in-1-IgG, IgG-ScFv, scFv2-Fc, a bi-nanobody, tanden antibody, a DART-Fc, a scFv-HAS-scFv, a DAF (two-in-one or four-in-one), a DNL-Fab3, knobs-in-holes common LC, knobs-in-holes assembly, a TandAb, a Triple Body, a miniantibody, a minibody, a TriBi minibody, a scFv-CH3 KIH, a Fab-scFv, a scFv-CH-CL-scFv, a F(ab′)2-scFV2, a scFv-KIH, a Fab-scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a tandem scFv-Fc, an intrabody, a dock and lock bispecific antibody, an ImmTAC, a HSAbody, a tandem scFv, an IgG-IgG, a Cov-X-Body, and a scFv1-PEG-scFv2.

Non-limiting examples of an antigen-binding fragment of an antibody include an Fv fragment, a Fab fragment, a F(ab′)2 fragment, and a Fab′ fragment. Additional examples of an antigen-binding fragment of an antibody is an antigen-binding fragment of an antigen-binding fragment of an IgA (e.g., an antigen-binding fragment of IgA1 or IgA2) (e.g., an antigen-binding fragment of a human or humanized IgA, e.g., a human or humanized IgA1 or IgA2); an antigen-binding fragment of an IgD (e.g., an antigen-binding fragment of a human or humanized IgD); an antigen-binding fragment of an IgE (e.g., an antigen-binding fragment of a human or humanized IgE); an IgG (e.g., an antigen-binding fragment of IgG1, IgG2, IgG3, or IgG4) (e.g., an antigen-binding fragment of a human or humanized IgG, e.g., human or humanized IgG1, IgG2, IgG3, or IgG4); or an antigen-binding fragment of an IgM (e.g., an antigen-binding fragment of a human or humanized IgM).

Non-limiting examples of anti-TNFα agents that are antibodies that specifically bind to TNFα are described in Ben-Horin et al., Autoimmunity Rev. 13(1):24-30, 2014; Bongartz et al., JAMA 295(19):2275-2285, 2006; Butler et al., Eur. Cytokine Network 6(4):225-230, 1994; Cohen et al., Canadian J. Gastroenterol. Hepatol. 15(6):376-384, 2001; Elliott et al., Lancet 1994; 344: 1125-1127, 1994; Feldmann et al., Ann. Rev. Immunol. 19(1):163-196, 2001; Rankin et al., Br. J Rheumatol. 2:334-342, 1995; Knight et al., Molecular Immunol. 30(16):1443-1453, 1993; Lorenz et al., J. Immunol. 156(4):1646-1653, 1996; Hinshaw et al., Circulatory Shock 30(3):279-292, 1990; Ordas et al., Clin. Pharmacol. Therapeutics 91(4):635-646, 2012; Feldman, Nature Reviews Immunol. 2(5):364-371, 2002; Taylor et al., Nature Reviews Rheumatol. 5(10):578-582, 2009; Garces et al., Annals Rheumatic Dis. 72(12):1947-1955, 2013; Palladino et al., Nature Rev. Drug Discovery 2(9):736-746, 2003; Sandborn et al., Inflammatory Bowel Diseases 5(2):119-133, 1999; Atzeni et al., Autoimmunity Reviews 12(7):703-708, 2013; Maini et al., Immunol. Rev. 144(1):195-223, 1995; Wanner et al., Shock 11(6):391-395, 1999; and U.S. Pat. Nos. 6,090,382; 6,258,562; and 6,509,015).

In certain embodiments, the anti-TNFα agent can include or is golimumab (golimumab™), adalimumab (Humira™), infliximab (Remicade™), CDP571, CDP 870, or certolizumab pegol (Cimzia™). In certain embodiments, the anti-TNFα agent can be a TNFα inhibitor biosimilar. Examples of approved and late-phase TNFα inhibitor biosimilars include, but are not limited to, infliximab biosimilars such as Flixabi™ (SB2) from Samsung Bioepis, Inflectra® (CT-P13) from Celltrion/Pfizer, GS071 from Aprogen, Remsima™, PF-06438179 from Pfizer/Sandoz, NI-071 from Nichi-Iko Pharmaceutical Co., and ABP 710 from Amgen; adalimumab biosimilars such as Amgevita® (ABP 501) from Amgen and Exemptia™ from Zydus Cadila, BMO-2 or MYL-1401-A from Biocon/Mylan, CHS-1420 from Coherus, FKB327 from Kyowa Kirin, and BI 695501 from Boehringer Ingelheim; Solymbic®, SB5 from Samsung Bioepis, GP-2017 from Sandoz, ONS-3010 from Oncobiologics, M923 from Momenta, PF-06410293 from Pfizer, and etanercept biosimilars such as Erelzi™ from Sandoz/Novartis, Brenzys™ (SB4) from Samsung Bioepis, GP2015 from Sandoz, TuNEX® from Mycenax, LBEC0101 from LG Life, and CHS-0214 from Coherus.

In some embodiments of any of the methods described herein, the anti-TNFα agent is selected from the group consisting of: adalimumab, certolizumab, etanercept, golimumab, infliximabm, CDP571, and CDP 870.

In some embodiments, any of the antibodies or antigen-binding fragments described herein has a dissociation constant (K_(D)) of less than 1×10⁻⁵ M (e.g., less than 0.5×10⁻⁵ M, less than 1×10⁻⁶ M, less than 0.5×10⁻⁶ M, less than 1×10⁻⁷ M, less than 0.5×10⁻⁷ M, less than 1×10⁻⁸ M, less than 0.5×10⁻⁸ M, less than 1×10⁻⁹ M, less than 0.5×10⁻⁹ M, less than 1×10⁻¹⁰ M, less than 0.5×10⁻¹⁰ M, less than 1×10⁻¹¹ M, less than 0.5×10⁻¹¹ M, or less than 1×10⁻¹² M), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR).

In some embodiments, any of the antibodies or antigen-binding fragments described herein has a K_(D) of about 1×10⁻¹² M to about 1×10⁻⁵ M, about 0.5×10⁻⁵ M, about 1×10⁻⁶ M, about 0.5×10⁻⁶ M, about 1×10⁻⁷ M, about 0.5×10⁻⁷ M, about 1×10⁻⁸ M, about 0.5×10⁻⁸ M, about 1×10⁻⁹ M, about 0.5×10⁻⁹ M, about 1×10⁻¹⁰ M, about 0.5×10⁻¹⁰ M, about 1×10⁻¹¹ M, or about 0.5×10⁻¹¹ M (inclusive); about 0.5×10⁻¹¹ M to about 1×10⁻⁵ M, about 0.5×10⁻⁵ M, about 1×10⁻⁶ M, about 0.5×10⁻⁶ M, about 1×10⁻⁷ M, about 0.5×10⁻⁷ M, about 1×10⁻⁸ M, about 0.5×10⁻⁸ M, about 1×10⁻⁹ M, about 0.5×10⁻⁹ M, about 1×10⁻¹⁰ M, about 0.5×10⁻¹⁰ M, or about 1×10⁻¹¹ M (inclusive); about 1×10⁻¹¹ M to about 1×10⁻⁵ M, about 0.5×10⁻⁵ M, about 1×10⁻⁶ M, about 0.5×10⁻⁶ M, about 1×10⁻⁷ M, about 0.5×10⁻⁷ M, about 1×10⁻⁸ M, about 0.5×10⁻⁸ M, about 1×10⁻⁹ M, about 0.5×10⁻⁹ M, about 1×10⁻¹⁰ M, or about 0.5×10⁻¹⁰ M (inclusive); about 0.5×10⁻¹⁰ M to about 1×10⁻⁵ M, about 0.5×10⁻⁵ M, about 1×10⁻⁶ M, about 0.5×10⁻⁶ M, about 1×10⁻⁷ M, about 0.5×10⁻⁷ M, about 1×10⁻⁸ M, about 0.5×10⁻⁸ M, about 1×10⁻⁹ M, about 0.5×10⁻⁹ M, or about 1×10⁻¹⁰ M (inclusive); about 1×10⁻¹⁰ M to about 1×10⁻⁵ M, about 0.5×10⁻⁵ M, about 1×10⁻⁶ M, about 0.5×10⁻⁶ M, about 1×10⁻⁷ M, about 0.5×10⁻⁷ M, about 1×10⁻⁸ M, about 0.5×10⁻⁸ M, about 1×10⁻⁹ M, or about 0.5×10⁻⁹ M (inclusive); about 0.5×10⁻⁹ M to about 1×10⁻⁵ M, about 0.5×10⁻⁵ M, about 1×10⁻⁶ M, about 0.5×10⁻⁶ M, about 1×10⁻⁷ M, about 0.5×10⁻⁷ M, about 1×10⁻⁸ M, about 0.5×10⁻⁸ M, or about 1×10⁻⁹ M (inclusive); about 1×10⁻⁹ M to about 1×10⁻⁵ M, about 0.5×10⁻⁵ M, about 1×10⁻⁶ M, about 0.5×10⁻⁶ M, about 1×10⁻⁷ M, about 0.5×10⁻⁷ M, about 1×10⁻⁸ M, or about 0.5×10⁻⁸ M (inclusive); about 0.5×10⁻⁸ M to about 1×10⁻⁵ M, about 0.5×10⁻⁵ M, about 1×10⁻⁶ M, about 0.5×10⁻⁶ M, about 1×10⁻⁷ M, about 0.5×10⁻⁷ M, or about 1×10⁻⁸ M (inclusive); about 1×10⁻⁸ M to about 1×10⁻⁵ M, about 0.5×10⁻⁵ M, about 1×10⁻⁶ M, about 0.5×10⁻⁶ M, about 1×10⁻⁷ M, or about 0.5×10⁻⁷ M (inclusive); about 0.5×10⁻⁷ M to about 1×10⁻⁵ M, about 0.5×10⁻⁵ M, about 1×10⁻⁶ M, about 0.5×10⁻⁶ M, or about 1×10⁻⁷ M (inclusive); about 1×10⁻⁷ M to about 1×10⁻⁵ M, about 0.5×10⁻⁵ M, about 1×10⁻⁶ M, or about 0.5×10⁻⁶ M (inclusive); about 0.5×10⁻⁶ M to about 1×10⁻⁵ M, about 0.5×10⁻⁵ M, or about 1×10⁻⁶ M (inclusive); about 1×10⁻⁶ M to about 1×10⁻⁵ M or about 0.5×10⁻⁵ M (inclusive); or about 0.5×10⁻⁵ M to about 1×10⁻⁵ M (inclusive), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR).

In some embodiments, any of the antibodies or antigen-binding fragments described herein has a K_(off) of about 1×10⁻⁶ s⁻¹ to about 1×10⁻³ s⁻¹, about 0.5×10⁻³ s⁻¹, about 1×10⁻⁴ s⁻¹, about 0.5×10⁻⁴ s⁻¹, about 1×10⁻⁵ s⁻¹, or about 0.5×10⁻⁵ s⁻¹ (inclusive); about 0.5×10⁻⁵ s⁻¹ to about 1×10⁻³ s⁻¹, about 0.5×10⁻³ s⁻¹, about 1×10⁻⁴ s⁻¹, about 0.5×10⁻⁴ s⁻¹, or about 1×10⁻⁵s⁻¹ (inclusive); about 1×10⁻⁵ s⁻¹ to about 1×10⁻³ s⁻¹, about 0.5×10⁻³ s⁻¹, about 1×10⁻⁴ s⁻¹, or about 0.5×10⁻⁴ s⁻¹ (inclusive); about 0.5×10⁻⁴ s⁻¹ to about 1×10⁻³ s⁻¹, about 0.5×10⁻³ s⁻¹, or about 1×10⁻⁴ s⁻¹ (inclusive); about 1×10⁻⁶ s⁻¹ to about 1×10⁻³ s⁻¹, or about 0.5×10⁻³ s⁻¹ (inclusive); or about 0.5×10⁻⁵ s⁻¹ to about 1×10⁻³ s⁻¹ (inclusive), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR).

In some embodiments, any of the antibodies or antigen-binding fragments described herein has a K_(on) of about 1×10² M⁻¹s⁻¹ to about 1×10⁶ M⁻¹s⁻¹, about 0.5×10⁶ M⁻¹s⁻¹, about 1×10⁵ M⁻¹s⁻¹, about 0.5×10⁵ M⁻¹s⁻¹, about 1×10⁴ M⁻¹s⁻¹, about 0.5×10⁴ M⁻¹s⁻¹, about 1×10³ M⁻¹s⁻¹, or about 0.5×10³ M⁻¹s⁻¹ (inclusive); about 0.5×10³ M⁻¹s⁻¹ to about 1×10⁶ M⁻¹s⁻¹, about 0.5×10⁶ M⁻¹s⁻¹, about 1×10⁵ M⁻¹s⁻¹, about 0.5×10⁵ M⁻¹s⁻¹, about 1×10⁴ M⁻¹s⁻¹, about 0.5×10⁴ M⁻¹s⁻¹, or about 1×10³ M⁻¹s⁻¹ (inclusive); about 1×10³ M⁻¹s⁻¹to about 1×10⁶ M⁻¹s⁻¹, about 0.5×10⁶ M⁻¹s⁻¹, about 1×10⁵ M⁻¹s⁻¹, about 0.5×10⁵ M⁻¹s⁻¹, about 1×10⁴ M⁻¹s⁻¹, or about 0.5×10⁴ M⁻¹s⁻¹ (inclusive); about 0.5×10⁴ M⁻¹s⁻¹ to about 1×10⁶ M⁻¹s^(−1,)about 0.5×10⁶ M⁻¹s⁻¹, about 1×10⁵ M⁻¹s⁻¹, about 0.5×10⁵ M⁻¹s⁻¹, or about 1×10⁴ M⁻¹s⁻¹(inclusive); about 1×10⁴ M⁻¹s⁻¹to about 1×10⁶ M⁻¹s⁻¹, about 0.5×10⁶ M⁻¹s⁻¹, about 1×10⁵ M⁻¹s⁻¹, or about 0.5×10⁵ M⁻¹s⁻¹ (inclusive); about 0.5×10⁵ M⁻¹s⁻¹ about 1×10⁶ M⁻¹s⁻¹, about 0.5×10⁶ M⁻¹s⁻¹, or about 1×10⁵ M⁻¹s⁻¹ (inclusive); about 1×10⁵ M⁻¹s⁻¹ to about 1×10⁶ M⁻¹s⁻¹, or about 0.5×10⁶ M⁻¹s⁻¹ (inclusive); or about 0.5×10⁶ M⁻¹s⁻¹ to about 1×10⁶ M⁻¹s⁻¹ (inclusive), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR).

Fusion Proteins

In some embodiments, the anti-TNFα agent is a fusion protein (e.g., an extracellular domain of a TNFR fused to a partner peptide, e.g., an Fc region of an immunoglobulin, e.g., human IgG) (see, e.g., Deeg et al., Leukemia 16(2):162, 2002; Peppel et al., J. Exp. Med. 174(6):1483-1489, 1991) or a soluble TNFR (e.g., TNFR1 or TNFR2) that binds specifically to TNFα. In some embodiments, the anti-TNFα agent includes or is a soluble TNFα receptor (e.g., Bjornberg et al., Lymphokine Cytokine Res. 13(3):203-211, 1994; Kozak et al., Am. J. Physiol. Reg. Integrative Comparative Physiol. 269(1):R23-R29, 1995; Tsao et al., Eur Respir J. 14(3):490-495, 1999; Watt et al., J Leukoc Biol. 66(6):1005-1013, 1999; Mohler et al., J. Immunol. 151(3):1548-1561, 1993; Nophar et al., EMBO J. 9(10):3269, 1990; Piguet et al., Eur. Respiratory J. 7(3):515-518, 1994; and Gray et al., Proc. Natl. Acad. Sci. U.S.A. 87(19):7380-7384, 1990). In some embodiments, the anti-TNFα agent includes or is etanercept (Enbrel™) (see, e.g., WO 91/03553 and WO 09/406,476, incorporated by reference herein). In some embodiments, the anti-TNFα agent inhibitor includes or is r-TBP-I (e.g., Gradstein et al., J. Acquir. Immune Defic. Syndr. 26(2): 111-117, 2001).

Inhibitory Nucleic Acids

An antisense nucleic acid molecule can be fully or partially complementary to all or part of a non-coding region of the coding strand of a nucleotide sequence encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein. Non-coding regions (5′ and 3′ untranslated regions) are the 5′ and 3′ sequences that flank the coding region in a gene and are not translated into amino acids.

Based upon the sequences disclosed herein, one of skill in the art can easily choose and synthesize any of a number of appropriate antisense nucleic acids to target a nucleic acid encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein described herein. Antisense nucleic acids targeting a nucleic acid encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein can be designed using the software available at the Integrated DNA Technologies website.

An antisense nucleic acid can be, for example, about 5, 10, 15, 18, 20, 22, 24, 25, 26, 28, 30, 32, 35, 36, 38, 40, 42, 44, 45, 46, 48, or 50 nucleotides or more in length. An antisense oligonucleotide can be constructed using enzymatic ligation reactions and chemical synthesis using procedures known in the art. For example, an antisense nucleic acid can be chemically synthesized using variously modified nucleotides or naturally occurring nucleotides designed to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides or to increase the biological stability of the molecules.

Examples of modified nucleotides which can be used to generate an antisense nucleic acid include 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid

-   -   (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine,         5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil,         hypoxanthine, xanthine, 4-acetylcytosine,         5-(carboxyhydroxylmethyl) uracil,         5-carboxymethylaminomethyl-2-thiouridine,         5-carboxymethylaminomethyluracil, dihydrouracil,         beta-D-galactosylqueosine, inosine, N6-isopentenyladenine,         5-methylcytosine, N6-adenine, 7-methylguanine,         5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil,         beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil,         5-methoxyuracil, 5-methyl-2-thiouracil, 2-thiouracil,         4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid         methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil,         3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and         2,6-diaminopurine. Alternatively, the antisense nucleic acid can         be produced biologically using an expression vector into which a         nucleic acid has been subcloned in an antisense orientation         (i.e., RNA transcribed from the inserted nucleic acid will be of         an antisense orientation to a target nucleic acid of interest).

The antisense nucleic acid molecules described herein can be prepared in vitro and administered to a subject, e.g., a human subject. Alternatively, they can be generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein to thereby inhibit expression, e.g., by inhibiting transcription and/or translation. The hybridization can be by conventional nucleotide complementarities to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix. The antisense nucleic acid molecules can be delivered to a mammalian cell using a vector (e.g., an adenovirus vector, a lentivirus, or a retrovirus).

An antisense nucleic acid can be an a-anomeric nucleic acid molecule. An a-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual, (3-units, the strands run parallel to each other (Gaultier et al., Nucleic Acids Res. 15:6625-6641, 1987). The antisense nucleic acid can also comprise a chimeric RNA-DNA analog (Inoue et al., FEBS Lett. 215:327-330, 1987) or a 2′-O-methylribonucleotide (Inoue et al., Nucleic Acids Res. 15:6131-6148, 1987).

Another example of an inhibitory nucleic acid is a ribozyme that has specificity for a nucleic acid encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA, e.g., specificity for any one of the sequences presented in Table E). Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes (described in Haselhoff and Gerlach, Nature 334:585-591, 1988)) can be used to catalytically cleave mRNA transcripts to thereby inhibit translation of the protein encoded by the mRNA. An AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et al., Science 261:1411-1418, 1993.

Alternatively, a ribozyme having specificity for an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA can be designed based upon the nucleotide sequence of any of the AP-1, ASK1, CD14, c-jun, ERK1/2, IxB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA sequences disclosed herein (e.g., in Table E). For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA (see, e.g., U.S. Pat. Nos. 4,987,071 and 5,116,742).

An inhibitory nucleic acid can also be a nucleic acid molecule that forms triple helical structures. For example, expression of an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP polypeptide can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the gene encoding the AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP polypeptide (e.g., the promoter and/or enhancer, e.g., a sequence that is at least 1 kb, 2 kb, 3 kb, 4 kb, or 5 kb upstream of the transcription initiation start state) to form triple helical structures that prevent transcription of the gene in target cells. See generally Maher, Bioassays 14(12):807-15, 1992; Helene, Anticancer Drug Des. 6(6):569-84, 1991; and Helene, Ann. N.Y. Acad. Sci. 660:27-36, 1992.

In various embodiments, inhibitory nucleic acids can be modified at the sugar moiety, the base moiety, or phosphate backbone to improve, e.g., the solubility, stability, or hybridization, of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids (see, e.g., Hyrup et al., Bioorganic Medicinal Chem. 4(1):5-23, 1996). Peptide nucleic acids (PNAs) are nucleic acid mimics, e.g., DNA mimics, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of PNAs allows for specific hybridization to RNA and DNA under conditions of low ionic strength. PNA oligomers can be synthesized using standard solid phase peptide synthesis protocols (see, e.g., Perry-O'Keefe et al., Proc. Natl. Acad. Sci. U.S.A. 93:14670-675, 1996). PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication.

An antisense nucleic acid molecule can be fully or partially complementary to all or part of a non-coding region of the coding strand of a nucleotide sequence encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein. Non-coding regions (5′ and 3′ untranslated regions) are the 5′ and 3′ sequences that flank the coding region in a gene and are not translated into amino acids.

Based upon the sequences disclosed herein, one of skill in the art can easily choose and synthesize any of a number of appropriate antisense nucleic acids to target a nucleic acid encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein described herein. Antisense nucleic acids targeting a nucleic acid encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein can be designed using the software available at the Integrated DNA Technologies website.

An antisense nucleic acid can be, for example, about 5, 10, 15, 18, 20, 22, 24, 25, 26, 28, 30, 32, 35, 36, 38, 40, 42, 44, 45, 46, 48, or 50 nucleotides or more in length. An antisense oligonucleotide can be constructed using enzymatic ligation reactions and chemical synthesis using procedures known in the art. For example, an antisense nucleic acid can be chemically synthesized using variously modified nucleotides or naturally occurring nucleotides designed to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides or to increase the biological stability of the molecules.

Examples of modified nucleotides which can be used to generate an antisense nucleic acid include 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 5-methoxyuracil, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest).

The antisense nucleic acid molecules described herein can be prepared in vitro and administered to a subject, e.g., a human subject. Alternatively, they can be generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein to thereby inhibit expression, e.g., by inhibiting transcription and/or translation. The hybridization can be by conventional nucleotide complementarities to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix. The antisense nucleic acid molecules can be delivered to a mammalian cell using a vector (e.g., an adenovirus vector, a lentivirus, or a retrovirus).

An antisense nucleic acid can be an a-anomeric nucleic acid molecule. An α-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual, β-units, the strands run parallel to each other (Gaultier et al., Nucleic Acids Res. 15:6625-6641, 1987). The antisense nucleic acid can also comprise a chimeric RNA-DNA analog (Inoue et al., FEBS Lett. 215:327-330, 1987) or a 2′-O-methylribonucleotide (Inoue et al., Nucleic Acids Res. 15:6131-6148, 1987).

Another example of an inhibitory nucleic acid is a ribozyme that has specificity for a nucleic acid encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA, e.g., specificity for any one of the sequences presented in Table E). Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes (described in Haselhoff and Gerlach, Nature 334:585-591, 1988)) can be used to catalytically cleave mRNA transcripts to thereby inhibit translation of the protein encoded by the mRNA. An AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et al., Science 261:1411-1418, 1993.

Alternatively, a ribozyme having specificity for an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA can be designed based upon the nucleotide sequence of any of the AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA sequences disclosed herein (e.g., in Table E). For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA (see, e.g., U.S. Pat. Nos. 4,987,071 and 5,116,742).

An inhibitory nucleic acid can also be a nucleic acid molecule that forms triple helical structures. For example, expression of an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP polypeptide can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the gene encoding the AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, INK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP polypeptide (e.g., the promoter and/or enhancer, e.g., a sequence that is at least 1 kb, 2 kb, 3 kb, 4 kb, or 5 kb upstream of the transcription initiation start state) to form triple helical structures that prevent transcription of the gene in target cells. See generally Maher, Bioassays 14(12):807-15, 1992; Helene, Anticancer Drug Des. 6(6):569-84, 1991; and Helene, Ann. N.Y. Acad. Sci. 660:27-36, 1992.

In various embodiments, inhibitory nucleic acids can be modified at the sugar moiety, the base moiety, or phosphate backbone to improve, e.g., the solubility, stability, or hybridization, of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids (see, e.g., Hyrup et al., Bioorganic Medicinal Chem. 4(1):5-23, 1996). Peptide nucleic acids (PNAs) are nucleic acid mimics, e.g., DNA mimics, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of PNAs allows for specific hybridization to RNA and DNA under conditions of low ionic strength. PNA oligomers can be synthesized using standard solid phase peptide synthesis protocols (see, e.g., Perry-O'Keefe et al., Proc. Natl. Acad. Sci. U.S.A. 93:14670-675, 1996). PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication.

Inhibitory nucleic acids that can decrease the expression of AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA expression in a mammalian cell include antisense nucleic acid molecules, i.e., nucleic acid molecules whose nucleotide sequence is fully or partially complementary to all or part of a AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA (e.g., fully or partially complementary to all or a part of any one of the sequences presented in Table E).

TABLE E mRNA GenBank Human gene accession number(s) Tumor necrosis factor (TNF, a.k.a. TNF- NM_000594 alpha) TNF receptor superfamily member 1A NM_001065 (TNFRSF1A) (a.k.a. TNFR1) NM_001346091 NM_001346092 TNF receptor superfamily member 1B NM_001066 (TNFRSF1B) (a.k.a. TNFR2) XM_011542060 XM_011542063 XM_017002214 XM_017002215 XM_017002211 TNFRSF1A associated via death domain NM_003789 (TRADD) NM_001323552 XM_005256213 XM_017023815 TNF receptor associated factor 2 (TRAF2) NM_021138 XM_011518976 XM_011518977 XM_011518974 JunD proto-oncogene, AP-1 transcription NM_001286968 factor subunit (JUND) NM_005354 Mitogen-activated protein kinase kinase NM_005923 kinase 5 (MAP3K5) (a.k.a. ASK1) XM_017010875 XM_017010872 XM_017010873 XM_017010877 XM_017010874 XM_017010871 XM_017010870 XM_017010876 XM_011535839 CD14 NM_000591 NM_001040021 NM_001174104 NM_001174105 Mitogen-activated protein kinase 3 NM_001040056 (MAPK3) (a.k.a. ERK1) NM_001109891 NM_002746 Mitogen-activated protein kinase 1 NM_002745 (MAPK1) (a.k.a. ERK2) NM_138957 Inhibitor of nuclear factor kappa B kinase NM_001190720 subunit beta (IKBKB) NM_001242778 NM_001556 XM_005273491 XM_005273496 XM_005273493 XM_005273498 XM_011544518 XM_005273492 XM_005273490 XM_005273494 12XM_017013396 XM_011544521 XM_011544522 XM_005273495 XM_011544517 XM_011544520 XM_011544519 NFKB inhibitor alpha (NFKBIA) NM_020529 Interleukin 1 receptor associated kinase 1 NM_001025242 (IRAK1) NM_001025243 NM_001569 XM_005274668 Mitogen-activated protein kinase 8 NM_001278547 (MAPK8) (a.k.a. JNK) NM_001278548 NM_001323302 NM_001323320 NM_001323321 NM_001323322 NM_001323323 NM_001323324 NM_001323325 NM_001323326 NM_001323327 NM_001323328 NM_001323329 NM_001323330 NM_001323331 NM_139046 NM_139049 XM_024448079 XM_024448080 Lipopolysaccharide binding protein (LBP) NM_004139 Mitogen-activated protein kinase kinase 1 NM_002755 (MAP2K1) (a.k.a. MEK1) XM_017022411 XM_011521783 XM_017022412 XM_017022413 Mitogen-activated protein kinase kinase 2 NM_030662 (MAP2K2) (a.k.a. MEK2) XM_006722799 XM_017026990 XM_017026989 XM_017026991 Mitogen-activated protein kinase kinase 3 NM_001316332 (MAP2K3) (a.k.a. MEK3) NM_002756 NM_145109 XM_017024859 XM_005256723 XM_017024857 XM_011523959 XM_017024858 XM_011523958 Mitogen-activated protein kinase kinase 6 NM_001330450 (MAP2K6) (a.k.a. MEK6) NM_002758 XM_005257516 XM_011525027 XM_011525026 XM_006721975 Mitogen-activated protein kinase kinase NM_005921 kinase 1 (MAP3K1) (a.k.a. MEKK1) XM_017009485 XM_017009484 Mitogen-activated protein kinase kinase NM_001330431 kinase 3 (MAP3K3) (a.k.a. MEKK3) NM_001363768 NM_002401 NM_203351 XM_005257378 Mitogen-activated protein kinase kinase NM_001291958 kinase 4 (MAP3K4) (a.k.a. MEKK4) NM_001301072 NM_001363582 NM_005922 NM_006724 XM_017010869 Mitogen-activated protein kinase kinase NM_001297609 kinase 6 (MAP3K6) (a.k.a. MEKK6) NM_004672 XM_017002771 XM_017002772 Mitogen-activated protein kinase kinase NM_003188 kinase 7 (MAP3K7) (a.k.a. MEKK7) NM_145331 NM_145332 NM_145333 XM_006715553 XM_017011226 MAPK activated protein kinase 2 NM_004759 (MAPKAPK2) (a.k.a. MK2) NM_032960 XM_005273353 XM_017002810 MYD88, innate immune signal transduction NM_001172566 adaptor (MYD88) NM_001172567 NM_001172568 NM_001172569 NM_001365876 NM_001365877 NM_002468 Nuclear factor kappa B subunit 1 (NFKB1) NM_001165412 NM_001319226 NM_003998 XM_024454069 XM_024454067 XM_011532006 XM_024454068 Mitogen-activated protein kinase kinase NM_003954 kinase 14 (MAP3K14) (a.k.a. NIK) XM_011525441 Mitogen-activated protein kinase 14 NM_001315 (MAPK14) (a.k.a. p38) NM_139012 NM_139013 NM_139014 XM_011514310 XM_017010300 XM_017010299 XM_017010301 XM_017010304 XM_017010303 XM_017010302 XM_006714998 Eukaryotic translation initiation factor 2 NM_001135651 alpha kinase 2 (EIF2AK2) (a.k.a. PKR) NM_001135652 NM_002759 XM_011532987 XM_017004503 AKT serine/threonine kinase 1 (AKT1) NM_001014431 (a.k.a. RAC) NM_001014432 NM_005163 Zinc fingers and homeoboxes 2 (ZHX2) NM_001362797 (a.k.a. RAF) NM_014943 XM_011516932 XM_005250836 KRAS proto-oncogene, GTPase (KRAS) NM_001369786 NM_001369787 NM_004985 NM_033360 NRAS proto-oncogene, GTPase (NRAS) NM_002524 Receptor interacting serine/threonine kinase NM_001317061 1 (RIPK1) (a.k.a. RIP) NM_001354930 NM_001354931 NM_001354932 NM_001354933 NM_001354934 NM_003804 XM_017011405 XM_006715237 XM_017011403 XM_017011404 TNF receptor associated factor 6 (TRAF6) NM_004620 NM_145803 XM_017018220 ZFP36 ring finger protein (ZFP36) (a.k.a. NM_003407 TTP)

Small Molecules

In some embodiments, the anti-TNFα agent is a small molecule. In some embodiments, the small molecule is a tumor necrosis factor-converting enzyme (TACE) inhibitor (e.g., Moss et al., Nature Clinical Practice Rheumatology 4: 300-309, 2008). In some embodiments, the anti-TNFα agent is C87 (Ma et al., J. Biol. Chem. 289(18):12457-66, 2014). In some embodiments, the small molecule is LMP-420 (e.g., Haraguchi et al., AIDS Res. Ther. 3:8, 2006). In some embodiments, the TACE inhibitor is TMI-005 and BMS-561392. Additional examples of small molecule inhibitors are described in, e.g., He et al., Science 310(5750):1022-1025, 2005.

In some examples, the anti-TNFα agent is a small molecule that inhibits the activity of one of AP-1, ASK1, IKK, JNK, MAPK, MEKK 1/4, MEKK4/7, MEKK 3/6, NIK, TRADD, RIP, NF-κB, and TRADD in a cell (e.g., in a cell obtained from a subject, a mammalian cell).

In some examples, the anti-TNFα agent is a small molecule that inhibits the activity of one of CD14, MyD88 (see, e.g., Olson et al., Scientific Reports 5:14246, 2015), ras (e.g., Baker et al., Nature 497:577-578, 2013), raf (e.g., vemurafenib (PLX4032, RG7204), sorafenib tosylate, PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265 (CHIR-265), AZ 628, NVP-BHG712, SB590885, ZM 336372, sorafenib, GW5074, TAK-632, CEP-32496, encorafenib (LGX818), CCT196969, LY3009120, RO5126766 (CH₅₁₂₆₇₆₆), PLX7904, and MLN2480).

In some examples, the anti-TNFα agent TNFα inhibitor is a small molecule that inhibits the activity of one of MK2 (PF 3644022 and PHA 767491), JNK (e.g., AEG 3482, BI 78D3, CEP 1347, c-JUN peptide, IQ 1S, JIP-1 (153-163), SP600125, SU 3327, and TCS JNK6o), c-jun (e.g., AEG 3482, BI 78D3, CEP 1347, c-JUN peptide, IQ 15, JIP-1 (153-163), SP600125, SU 3327, and TCS JNK6o), MEK3/6 (e.g., Akinleye et al., J. Hematol. Oncol. 6:27, 2013), p38 (e.g., AL 8697, AMG 548, BIRB 796, CMPD-1, DBM 1285 dihydrochloride, EO 1428, JX 401, ML 3403, Org 48762-0, PH 797804, RWJ 67657, SB 202190, SB 203580, SB 239063, SB 706504, SCIO 469, SKF 86002, SX 011, TA 01, TA 02, TAK 715, VX 702, and VX 745), PKR (e.g., 2-aminopurine or CAS 608512-97-6), TTP (e.g., CAS 329907-28-0), MEK1/2 (e.g., Facciorusso et al., Expert Review Gastroentrol. Hepatol. 9:993-1003, 2015), ERK1/2 (e.g., Mandal et al., Oncogene 35:2547-2561, 2016), NIK (e.g., Mortier et al., Bioorg. Med. Chem. Lett. 20:4515-4520, 2010), IKK (e.g., Reilly et al., Nature Med. 19:313-321, 2013), IκB (e.g., Suzuki et al., Expert. Opin. Invest. Drugs 20:395-405, 2011), NF-κB (e.g., Gupta et al., Biochim. Biophys. Acta 1799(10-12):775-787, 2010), rac (e.g., U.S. Pat. No. 9,278,956), MEK4/7, IRAK (Chaudhary et al., J. Med. Chem. 58(1):96-110, 2015), LBP (see, e.g., U.S. Pat. No. 5,705,398), and TRAF6 (e.g., 3-[(2,5-Dimethylphenyl)amino]-1-phenyl-2-propen-1-one).

In some embodiments of any of the methods described herein, the inhibitory nucleic acid can be about 10 nucleotides to about 50 nucleotides (e.g., about 10 nucleotides to about 45 nucleotides, about 10 nucleotides to about 40 nucleotides, about 10 nucleotides to about 35 nucleotides, about 10 nucleotides to about 30 nucleotides, about 10 nucleotides to about 28 nucleotides, about 10 nucleotides to about 26 nucleotides, about 10 nucleotides to about 25 nucleotides, about 10 nucleotides to about 24 nucleotides, about 10 nucleotides to about 22 nucleotides, about 10 nucleotides to about 20 nucleotides, about 10 nucleotides to about 18 nucleotides, about 10 nucleotides to about 16 nucleotides, about 10 nucleotides to about 14 nucleotides, about 10 nucleotides to about 12 nucleotides, about 12 nucleotides to about 50 nucleotides, about 12 nucleotides to about 45 nucleotides, about 12 nucleotides to about 40 nucleotides, about 12 nucleotides to about 35 nucleotides, about 12 nucleotides to about 30 nucleotides, about 12 nucleotides to about 28 nucleotides, about 12 nucleotides to about 26 nucleotides, about 12 nucleotides to about 25 nucleotides, about 12 nucleotides to about 24 nucleotides, about 12 nucleotides to about 22 nucleotides, about 12 nucleotides to about 20 nucleotides, about 12 nucleotides to about 18 nucleotides, about 12 nucleotides to about 16 nucleotides, about 12 nucleotides to about 14 nucleotides, about 15 nucleotides to about 50 nucleotides, about 15nucleotides to about 45 nucleotides, about 15nucleotides to about 40 nucleotides, about 15nucleotides to about 35 nucleotides, about 15 nucleotides to about 30 nucleotides, about 15nucleotides to about 28 nucleotides, about 15nucleotides to about 26 nucleotides, about 15nucleotides to about 25 nucleotides, about 15nucleotides to about 24 nucleotides, about 15nucleotides to about 22 nucleotides, about 15nucleotides to about 20 nucleotides, about 15nucleotides to about 18 nucleotides, about 15nucleotides to about 16 nucleotides, about 16 nucleotides to about 50 nucleotides, about 16 nucleotides to about 45 nucleotides, about 16 nucleotides to about 40 nucleotides, about 16 nucleotides to about 35 nucleotides, about 16 nucleotides to about 30 nucleotides, about 16 nucleotides to about 28 nucleotides, about 16 nucleotides to about 26 nucleotides, about 16 nucleotides to about 25 nucleotides, about 16 nucleotides to about 24 nucleotides, about 16 nucleotides to about 22 nucleotides, about 16 nucleotides to about 20 nucleotides, about 16 nucleotides to about 18 nucleotides, about 18 nucleotides to about 20 nucleotides, about 20 nucleotides to about 50 nucleotides, about 20 nucleotides to about 45 nucleotides, about 20 nucleotides to about 40 nucleotides, about 20 nucleotides to about 35 nucleotides, about 20 nucleotides to about 30 nucleotides, about 20 nucleotides to about 28 nucleotides, about 20 nucleotides to about 26 nucleotides, about 20 nucleotides to about 25 nucleotides, about 20 nucleotides to about 24 nucleotides, about 20 nucleotides to about 22 nucleotides, about 24 nucleotides to about 50 nucleotides, about 24 nucleotides to about 45 nucleotides, about 24 nucleotides to about 40 nucleotides, about 24 nucleotides to about 35 nucleotides, about 24 nucleotides to about 30 nucleotides, about 24 nucleotides to about 28 nucleotides, about 24 nucleotides to about 26 nucleotides, about 24 nucleotides to about 25 nucleotides, about 26 nucleotides to about 50 nucleotides, about 26 nucleotides to about 45 nucleotides, about 26 nucleotides to about 40 nucleotides, about 26 nucleotides to about 35 nucleotides, about 26 nucleotides to about 30 nucleotides, about 26 nucleotides to about 28 nucleotides, about 28 nucleotides to about 50 nucleotides, about 28 nucleotides to about 45 nucleotides, about 28 nucleotides to about 40 nucleotides, about 28 nucleotides to about 35 nucleotides, about 28 nucleotides to about 30 nucleotides, about 30 nucleotides to about 50 nucleotides, about 30 nucleotides to about 45 nucleotides, about 30 nucleotides to about 40 nucleotides, about 30 nucleotides to about 38 nucleotides, about 30 nucleotides to about 36 nucleotides, about 30 nucleotides to about 34 nucleotides, about 30 nucleotides to about 32 nucleotides, about 32 nucleotides to about 50 nucleotides, about 32 nucleotides to about 45 nucleotides, about 32 nucleotides to about 40 nucleotides, about 32 nucleotides to about 35 nucleotides, about 35 nucleotides to about 50 nucleotides, about 35 nucleotides to about 45 nucleotides, about 35 nucleotides to about 40 nucleotides, about 40 nucleotides to about 50 nucleotides, about 40 nucleotides to about 45 nucleotides, about 42 nucleotides to about 50 nucleotides, about 42 nucleotides to about 45 nucleotides, or about 45 nucleotides to about 50 nucleotides) in length. One skilled in the art will appreciate that inhibitory nucleic acids may comprises at least one modified nucleic acid at either the 5′ or 3′ end of DNA or RNA.

In some embodiments, the inhibitory nucleic acid can be formulated in a liposome, a micelle (e.g., a mixed micelle), a nanoemulsion, or a microemulsion, a solid nanoparticle, or a nanoparticle (e.g., a nanoparticle including one or more synthetic polymers). Additional exemplary structural features of inhibitory nucleic acids and formulations of inhibitory nucleic acids are described in US 2016/0090598.

In some embodiments, the inhibitory nucleic acid (e.g., any of the inhibitory nucleic acid described herein) can include a sterile saline solution (e.g., phosphate-buffered saline (PBS)). In some embodiments, the inhibitory nucleic acid (e.g., any of the inhibitory nucleic acid described herein) can include a tissue-specific delivery molecule (e.g., a tissue-specific antibody).

In one embodiment, provided herein is a combination of a compound of any preceding embodiment, for use in the treatment or the prevention of a condition mediated by TNF-α, in a patient in need thereof, wherein the compound is administered to said patient at a therapeutically effective amount. Preferably, the subject is resistant to treatment with an anti-TNFα agent. Preferably, the condition is a gut disease or disorder.

In one embodiment, provided herein is a pharmaceutical composition of comprising a compound of any preceding embodiment, and an anti-TNFα agent disclosed herein. Preferably wherein the anti-TNFα agent is Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab, more preferably wherein the anti-TNFα agent is Adalimumab.

In one embodiment, provided herein is a pharmaceutical combination of a compound of any preceding embodiment, and an anti-TNFα agent Preferably wherein the anti-TNFα agent is Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab, more preferably wherein the anti-TNFα agent is Adalimumab.

In one embodiment, the present invention relates to an NLRP3 antagonist for use in the treatment or the prevention of a condition mediated by TNF-α, in particular a gut disease or disorder, in a patient in need thereof, wherein the NLRP3 antagonist is administered to said patient at a therapeutically effective amount.

In one embodiment, the present invention relates to an NLRP3 antagonist for use in the treatment or the prevention of a condition, in particular a gut disease or disorder, in a patient in need thereof wherein the NLRP3 antagonist is administered to said patient at a therapeutically effective amount.

In one embodiment, the present invention relates to an NLRP3 antagonist for use in the treatment, stabilization or lessening the severity or progression of gut disease or disorder, in a patient in need thereof wherein the NLRP3 antagonist is administered to said patient at a therapeutically effective amount.

In one embodiment, the present invention relates to an NLRP3 antagonist for use in the slowing, arresting, or reducing the development of a gut disease or disorder, in a patient in need thereof wherein the NLRP3 antagonist is administered to said patient at a therapeutically effective amount.

In one embodiment, the present invention relates to an NLRP3 antagonist for use according to above listed embodiments wherein the NLRP3 antagonist is a gut-targeted NLRP3 antagonist.

In one embodiment, the present invention relates ton NLRP3 antagonist for use according to any of the above embodiments, wherein the gut disease is IBD.

In one embodiment, the present invention relates to an NLRP3 antagonist for use according to any of the above embodiments, wherein the gut disease is US or CD.

In one embodiment, the present invention relates to a method for the treatment or the prevention of a condition mediated by TNF-α, in particular a gut disease or disorder, in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a gut-targeted NLRP3 antagonist.

In one embodiment, the present invention relates to a method for the treatment or the prevention of a condition, in particular a gut disease or disorder, in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a gut-targeted NLRP3 antagonist.

In one embodiment, the present invention relates to a method for the treatment, stabilization or lessening the severity or progression of gut disease or disorder, in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a gut-targeted NLRP3 antagonist.

In one embodiment, the present invention relates to a method for slowing, arresting, or reducing the development of a gut disease or disorder, in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a gut-targeted NLRP3 antagonist.

In one embodiment, the present invention relates to a method according to any of the above embodiments, wherein the gut disease is IBD.

In one embodiment, the present invention relates to a method according to any of the above embodiments x to xx, wherein the gut disease is UC or CD.

In one embodiment, the present invention relates to a method for the treatment or the prevention of a condition mediated by TNF-α, in particular a gut disease or disorder, in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a gut-targeted NLRP3 antagonist.

Compound Preparation and Biological Assays

As can be appreciated by the skilled artisan, methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and RGM. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof

PREPARATIVE EXAMPLES

The following abbreviations have the indicated meanings:

-   ACN=acetonitrile -   BTC=trichloromethyl chloroformate -   Boc=t-butyloxy carbonyl -   Davephos=2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl -   DCM=dichloromethane -   DEA=diethylamine -   DMF═N,N-dimethylformamide -   DMSO=dimethyl sulfoxide -   DIEA═N,N-diisopropylethylamine -   DPPA=diphenylphosphoryl azide -   dppf=1,1′-Bis(diphenylphosphino)ferrocene -   EtOH=ethanol -   HATU=1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium     3-oxid hexafluorophosphate -   Hex=hexane -   HPLC=high performance liquid chromatography -   LC-MS=liquid chromatography-mass spectrometry -   LiHMDS=lithium bis(trimethylsilyl)amide -   LDA=lithium diisopropylamide -   M=mol/L -   Me=methyl -   MeOH=methanol -   MSA=methanesulfonic acid -   NBS=N-bromosuccinimide -   NCS=N-chlorosuccinimide -   NMR=nuclear magnetic resonance -   Pd(dppf)Cl₂=dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium -   Ph=phenyl -   PPh₃Cl₂=dichlorotriphenylphosphorane -   Py=pyridine -   RT=room temperature -   Rt=Retention time -   R_(f)=Retardation factor -   Sat.=saturated -   TBAF=tetrabutylammonium fluoride -   TBS=tert-butyldimethylsilyl -   TBSCl=tert-butyldimethylsilyl chloride -   TBDPSCl=tert-butyldiphenylsilyl chloride -   TEA=triethylamine -   TFA=trifluoroacetic acid -   THF=tetrahydrofuran -   TLC=thin layer chromatography -   TsOH=4-methylbenzenesulfonic acid -   UV=ultraviolet -   Burgess reagent=(Methoxycarbonylsulfamoyl)triethylammonium hydroxide     inner salt -   DIAD=Diisopropylazodicarboxylate -   DIBAL-H=Diisobutylaluminum hydride -   DPPA=Diphenylphosphoryl azide -   LAH=Lithium aluminum hydride -   NFSI=N-fluoro benzene sulfonamide -   NMO=4-Methylmorpholine N-oxide -   Pd(dtbpf)Cl₂=[1,1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) -   Ruphos=2-Dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl -   SEM-Cl=2-(Trimethylsilyl)ethoxymethyl chloride -   TsCl=4-Methylbenzenesulfonyl chloride -   TPAP=Tetrapropylammonium perruthenate

General

The progress of reactions was often monitored by TLC or LC-MS. The identity of the products was often confirmed by LC-MS. The LC-MS was recorded using one of the following methods.

Method A: Shim-pack XR-ODS, C18, 3×50 mm, 2.5 um column, 1.0 uL injection, 1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 5-100% (1.1 min), 100% (0.6 min) gradient with ACN (0.05% TFA) and water (0.05% TFA), 2 minute total run time.

Method B: Kinetex EVO, C18, 3×50 mm, 2.2 um column, 1.0 uL injection, 1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 10-95% (1.1 min), 95% (0.6 min) gradient with ACN and water (0.5% NH₄HCO₃), 2 minute total run time.

Method C: Shim-pack XR-ODS, C18, 3×50 mm, 2.5 um column, 1.0 uL injection, 1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 5-100% (2.1 min), 100% (0.6 min) gradient with ACN (0.05% TFA) and water (0.05% TFA), 3 minute total run time.

Method D: Kinetex EVO, C18, 3×50 mm, 2.2 um column, 1.0 uL injection, 1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 10-95% (2.1 min), 95% (0.6 min) gradient with ACN and water (0.5% NH₄HCO₃), 3 minute total run time.

Method F: Phenomenex, CHO-7644, Onyx Monolithic C18, 50×4.6 mm, 10.0 uL injection, 1.5 mL/min flow rate, 100-1500 amu scan range, 220 and 254 nm UV detection, 5% with ACN (0.1% TFA) to 100% water (0.1% TFA) over 9.5 min, with a stay at 100% (ACN, 0.1% TFA) for 1 min, then equilibration to 5% (ACN, 0.1% TFA) over 1.5 min.

The final targets were purified by Prep-HPLC. The Prep-HPLC was carried out using the following method.

Method E: Prep-HPLC: Column, XBridge Shield RP18 OBD (19×250 mm, 10 um); mobile phase, Water (10 mmol/L NH₄HCO₃) and ACN, UV detection 254/210 nm.

Method G: Prep-HPLC: Higgins Analytical Proto 200, C18 Column, 250×20 mm, 10 um; mobile phase, Water (0.1% TFA) and ACN (0.1% TFA), UV detection 254/210 nm.

NMR was recorded on BRUKER NMR 300.03 MHz, DUL-C-H, ULTRASHIELD™ 300, AVANCE II 300 B-ACS™ 120 or BRUKER NMR 400.13 MHz, BBFO, ULTRASHIELD™ 400, AVANCE III 400, B-ACS™ 120 or BRUKER AC 250 NMR instrument with TMS as reference measured in ppm (part per million).

Racemic compounds of this invention can be resolved to give individual enantiomers using a variety of known methods. For example, chiral stationary phases can used and the elution conditions can include normal phase or super-critical fluid with or without acidic or basic additives. Enantiomerically pure acids or bases can be used to form diatereomeric salts with the racemic compounds whereby pure enantiomers can be obtained by fractional crystallization. The racemates can also be derivatized with enantiomerically pure auxiliary reagents to form diastereomeric mixtures that can be separated. The auxiliary is then removed to give pure enantiomers.

Schemes for the Preparation of Final Targets:

Schemes 1-3 below illustrate several conditions used for coupling of sulfonimidamide 1 or 5 and isocyanate 2 to afford aminocarbonyl sulfonimidamide 4 via 3 or 6 after deprotection. As used in the schemes, rings “A” and “B” may be substituted as disclosed herein.

Scheme 4 below illustrates the coupling between sulfonimidamide 7 and isocyanate 2 to provide sulfonimidamide 8.

Scheme 5 below illustrates the conversion of carboxylic acid 9 through Curtius rearrangement to isocyanate 2 via acyl azide 10, whereupon coupling between 2 and sulfonimidamide 5 affords aminocarbonyl sulfonimidamide 4.

Scheme of final targets: Schemes below illustrate several conditions used for coupling of sulfonimidamide and isocyanate to afford aminocarbonyl sulfonimidamide.

Scheme of final targets: Schemes below illustrate several conditions used for coupling of sulfonimidamide and isocyanate or isocyanate equivalents to afford aminocarbonyl sulfonimidamide.

Schemes for the Preparation of Sulfonimidamide Intermediates 1-29:

Schemes below illustrate the preparation of sulfonamide intermediates.

Intermediate 1

N′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide Step 1: Methyl 5-(chlorosulfonyl)-2-methylfuran-3-carboxylate

Into a 500-mL 3-necked round-bottom flask was placed methyl 2-methylfuran-3-carboxylate (7 g, 50 mmol) in CHCl₃ (200 mL). This was followed by the addition of chlorosulfonic acid (11.6 g, 100 mmol) dropwise with stirring at −10° C. The reaction mixture was stirred for 48 h at RT, after which the system was cooled to −10° C. Then to the above was added phosphorus pentachloride (22.9 g, 110 mmol). The resulting solution was stirred for 0.5 h at 50° C. and then was quenched by pouring onto 200 mL of water/ice. The resulting mixture was extracted with 3×200 mL of DCM. The organic layers were combined and dried over anhydrous Na₂SO₄, and then concentrated under vacuum. This resulted in 7.5 g (crude, 63%) of the title compound as light brown oil. The crude product was used in the next step.

Step 2: Methyl 2-methyl-5-sulfamoylfuran-3-carboxylate

Into a 250-mL round-bottom flask was placed a solution of methyl 5-(chlorosulfonyl)-2-methylfuran-3-carboxylate (7.5 g, crude) in DCM (75 mL). To the above was added a saturated solution of ammonia in DCM (50 mL). The resulting solution was stirred for 3 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:4 to 1:2). This resulted in 5.0 g (46% over two steps) of the title compound as a light yellow solid. MS-ESI: 218.0 (M−1).

Step 3: 4-(2-Hydroxypropan-2-yl)-5-methylfuran-2-sulfonamide

Into a 250-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of methyl 2-methyl-5-sulfamoylfuran-3-carboxylate (3.7 g, 16.9 mmol) in THF (100 mL). This was followed by the addition of MeMgBr (3 M in THF, 25 mL) dropwise with stirring at −10° C. The resulting mixture was stirred for 10 h at RT and then was quenched by the addition of 50 mL of NH₄Cl (sat.). The resulting solution was extracted with 3×50 mL of ethyl acetate. The organic layers were combined and dried over anhydrous Na₂SO₄, then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:3 to 1:1). This resulted in 2.6 g (75%) of the title compound as a light yellow solid. MS-ESI: 218.0 (M−1).

Step 4: N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonamide

Into a 250-mL round-bottom flask purged with and maintained under nitrogen was placed 4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonamide (1.0 g, 4.56 mmol), DCM (100 mL), 1H-imidazole (612 mg, 9.12 mmol), and TBSCl (3.4 g, 22.6 mmol). The resulting solution was stirred for 14 h at RT and then was diluted with 100 mL of water. The resulting mixture was extracted with 3×50 mL of DCM and the organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:3). This resulted in 1.4 g (92%) of the title compound as a white solid. MS-ESI: 332.0 (M−1).

Step 5: N′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide

Into a 250-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed PPh₃Cl₂ (3.0 g, 10.2 mmol) in CHCl₃ (100 mL). This was followed by the addition of TEA (2.06 g, 20.4 mmol) dropwise with stirring at RT. After stirred at 0° C. for 10 min, to the above was added a solution of N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonamide (2.3 g, 6.8 mmol) in CHCl₃ (10 mL) dropwise with stirring at 0° C. The resulting solution was allowed to react for 30 min at 0° C. To the mixture was added a saturated solution of ammonia in DCM (10 mL) at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3×50 mL of DCM and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:3). This resulted in 0.80 g (52.8%) of the title compound as a light yellow solid. MS-ESI: 333.0 (M+1).

Intermediate 2

N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide Step 1: Methyl 2-mercaptothiazole-5-carboxylate

Into a 250-mL round-bottom flask was placed methyl 2-bromothiazole-5-carboxylate (10 g, 45 mmol), EtOH (100 mL), and sodium hydrogensulfide (5 g, 89 mmol). The resulting solution was stirred for 2 h at 80° C. and then was cooled to 0° C. with a water/ice bath. The pH value of the solution was adjusted to 3 with aq. HCl (1 N). The solids were collected by filtration. This resulted in 6 g (76%) of the title compound as a light yellow solid. MS-ESI: 176.0 (M+1).

Step 2: Methyl 2-(chlorosulfonyl)thiazole-5-carboxylate

Into a 250-mL round-bottom flask was placed methyl 2-mercaptothiazole-5-carboxylate (6 g, 34 mmol) and acetic acid (60 mL). This was followed by the addition of sodium hypochlorite (60 mL, 8%-10% wt.) in portions at 0° C. The resulting solution was stirred for 1 h at RT and then was diluted with 100 mL of water. The solution was extracted with 3×50 mL of DCM. The organic layers were combined and dried over anhydrous Na₂SO₄, then concentrated under vacuum. This resulted in 5 g (crude, 60%) of the title compound as yellow oil. The crude product was used in the next step.

Step 3-6 used similar procedure for converting compound 12 to Intermediate 1 shown in Scheme 6 to afford Intermediate 2. MS-ESI: 336.1 (M+1).

Intermediate 2

N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide Step 1: Methyl 2-mercaptothiazole-5-carboxylate

Into a 2-L round-bottom flask was placed methyl 2-bromothiazole-5-carboxylate (100 g, 450 mmol), EtOH (1000 mL), sodium hydrogensulfide (50 g, 890 mmol). The resulting solution was stirred for 2 h at 80° C. and then was cooled to 0° C. with a water/ice bath. The pH value of the solution was adjusted to 3 with hydrogen chloride (1 N). The solids were collected by filtration. This resulted in 63.2 g (80%) of the title compound as a light yellow solid. MS-ESI: 176.0 (M+1).

Step 2: Methyl 2-(chlorosulfonyl)thiazole-5-carboxylate

Into a 1-L round-bottom flask was placed methyl 2-mercaptothiazole-5-carboxylate (30 g, 170 mmol) and acetic acid (300 mL). This was followed by the addition of sodium hypochlorite (300 mL, 8%-10% wt.) in portions at 0° C. The resulting solution was stirred for 2 h at RT and then was diluted with 500 mL of water. The solution was extracted with 3×300 mL of DCM and the combined organic layers were washed with 2×300 mL of brine and dried over anhydrous Na₂SO₄. The crude product as a yellow solution in DCM was used in the next step.

Step 3: Methyl 2-sulfamoylthiazole-5-carboxylate

Into a 2-L round-bottom flask was placed methyl 2-(chlorosulfonyl)thiazole-5-carboxylate as a crude solution in DCM (900 mL). To the solution was introduced NH₃ (g) below 0° C. for 20 minutes. The resulting solution was stirred for 1 h at RT and then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in 23 g (75%, 2 steps) of the title compound as a white solid. MS-ESI: 223.0 (M+1).

Step 4: 5-(2-Hydroxypropan-2-yl)thiazole-2-sulfonamide

Into a 500-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of methyl 2-sulfamoylthiazole-5-carboxylate (15 g, 67.5 mmol) in THF (150 mL). This was followed by the addition of MeMgBr/THF (3 M, 90 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 14 h at RT and then was quenched by the addition of 100 mL of NH₄Cl (sat.). The resulting solution was extracted with 3×150 mL of DCM. The organic layers were combined and dried over anhydrous Na₂SO₄, then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in 11.5 g (78%) of the title compound as a white solid. MS-ESI: 223.0 (M+1), 221.0 (M−1) in positive and negative ion mode, respectively.

Step 5: N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonamide

Into a 250-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 5-(2-hydroxypropan-2-yl)thiazole-2-sulfonamide (5 g, 22.5 mmol) in THF (100 mL). Then to the above was added NaH (60% wt, 1.8 g, 45.0 mmol) in portions in an ice/water bath. After stirring for 20 minutes in a water/ice bath, this was followed by the addition of a solution of TBSCl (4.1 g, 27.2 mmol) in THF (10 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 4 h at RT. The reaction was quenched with sat. NH₄Cl (100 mL). The resulting solution was extracted with 3×100 mL of ethyl acetate and the combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. The crude solid was washed with ethyl acetate/hexane (1:5) (2×100 mL). This resulted in 6.81 g (90%) of the title compound as a yellow solid. MS-ESI: 337.1 (M+1), 335.1 (M−1) in positive and negative ion mode, respectively.

Step 6: N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide

Into a 100-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of PPh₃Cl₂ (3 g, 9.0 mmol) in CHCl₃ (100 mL). This was followed by the addition of DIEA (1.54 g, 11.9 mmol) dropwise with stirring at RT. The resulting solution was stirred for 10 min at RT. This was followed by the addition of a solution of N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonamide (2.0 g, 5.9 mmol) in CHCl₃ (30 mL) dropwise with stirring in an ice/water bath. The resulting solution was stirred for 30 min in an ice/water bath. To the above was introduced NH₃ (g) below 0° C. for 15 minutes. The resulting solution was stirred for 20 minutes at RT. The solids were filtered out and the filtrate was concentrated and the residue was dissolved in 300 mL of ethyl acetate. The solution was washed with brine (2×100 mL), dried over Na₂SO₄ and concentrated under vacuum. The crude solid was washed with CHCl₃ (100 mL). Then the filtrate was concentrated under vacuum and the residue was further purified by a silica gel column with ethyl acetate/petroleum ether (1:10 to 1:3). The original washed solid and solid from silica gel purification were combined. This resulted in 1.2 g (60%) of the title compound as a white solid. MS-ESI: 336.1 (M+1). ¹H-NMR (300 MHz, DMSO-d₆) δ 7.66 (s, 1H), 7.12 (s, 2H), 5.78 (s, 1H), 1.51 (s, 6H), 0.86 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H).

TABLE 2 The Intermediate in the following Table was prepared using the similar procedures for converting compound 16 to Intermediate 2 shown in Scheme 7B starting from ethyl 5-bromo-4- methylthiazole-2-carboxylate. Exact Intermediate # Structure IUPAC Name Mass [M + H]⁺ Intermediate 3

N′-(tert-butyldimethylsilyl)-2-(2- hydroxypropan-2-yl)-4- methylthiazole-5-sulfonimidamide 350.2

Intermediate 4

N′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylthiophene-2-sulfonimidamide

Steps 1-3 used similar procedures for converting compound 11 to compound 14 shown in Scheme 6 to afford compound 25 from compound 22. MS-ESI: 234.0 (M−1).

Steps 4-5 used similar procedure for converting compound 20 to Intermediate 2 shown in Scheme 7B to afford Intermediate 4 from compound 25. MS-ESI: 349.1 (M+1).

TABLE 3 The Intermediate in the following Table was prepared using similar procedure as shown in Scheme 8 above for converting compound 22 to Intermediate 4 starting from the appropriate materials. Exact Intermediate Mass # Structure IUPAC Name [M + H]⁺ Intermediate 5

N′-(tert-butyldimethylsilyl)-5-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide 335.1 Intermediate 6

N′-(tert-butyldimethylsilyl)-4-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide 335.1 Intermediate 7

N′-(tert-butyldimethylsilyl)-5-(2- hydroxypropan-2-yl)-3-methylthiophene-2- sulfonimidamide 349.1 Intermediate 8

N′-(tert-butyldimethylsilyl)-5-(2- hydroxypropan-2-yl)-4-methylthiophene-2- sulfonimidamide 349.1 Intermediate 9

N′-(tert-butyldimethylsilyl)-3-fluoro-5-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide 353.1 Intermediate 10

N′-(tert-butyldimethylsilyl)-4-(2- hydroxypropan-2-yl)furan-2- sulfonimidamide 319.1

Intermediate 11

N′-(tert-butyldimethylsilyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzenesulfonimidamide Step 1: Methyl 4-(chlorosulfonyl)-3-fluorobenzoate

Into a 1 L round-bottom flask was placed a solution of methyl 4-amino-3-fluorobenzoate (10 g, 59.1 mmol) in aq. HCl (6 N, 200 mL). This was followed by the addition of a solution of NaNO₂ (6.1 g, 88.8 mmol) in water (20 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 30 min at 0° C. The above mixture was added to a saturated solution of SO₂ in AcOH (200 mL) dropwise with stirring at 0° C. Then to the above was added CuCl₂ (8.0 g, 59.6 mmol). The resulting solution was stirred for 1 h at RT and was then quenched by the addition of 200 mL of water. The resulting solution was extracted with 3×200 mL of DCM. The organic layers were combined, dried over anhydrous Na₂SO₄ and concentrated under vacuum. This resulted in 10 g (67%) of the title compound as yellow oil. The product was used in the next step without further purification.

Step 2: Methyl 3-fluoro-4-sulfamoylbenzoate

Into a 1000 mL round bottom flask was placed a solution of methyl 4-(chlorosulfonyl)-3-fluorobenzoate solution (10 g, 39.5 mmol) in DCM (50 mL). This was followed by the addition of a saturated solution of ammonia in DCM (500 mL) in portions with stirring at 0° C. The resulting solution was stirred for 1 h at 0° C. The resulting solution was concentrated and the residue was purified with SiO₂-gel column and diluted with ethyl acetate/petroleum ether (1:2 to 1:1). This resulted in 8.28 g (90%) of the title compound as yellow solid. MS-ESI: 232.1 (M−1).

Step 3: 2-Fluoro-4-(2-hydroxypropan-2-yl)benzenesulfonamide

Into a 1 L 3-necked round-bottom flask was placed a solution of methyl 3-fluoro-4-sulfamoylbenzoate (8.28 g 35.5 mmol) in THF (500 mL). This was followed by the addition of MeMgBr/THF (3 M, 60 mL) dropwise with stirring at 0° C. The resulting solution was stirred overnight at RT and then was quenched by the addition of 100 mL of sat. NH₄Cl. The resulting solution was extracted with 3×200 mL of ethyl acetate and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2 to 1:1). This resulted 7.45 g (89.9%) of the title compound as a white solid. MS-ESI: 233.1 (M+1).

Step 4: N-(tert-butyldimethylsilyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzenesulfonamide

Into a 500 mL round bottom flask was placed a solution of 2-fluoro-4-(2-hydroxypropan-2-yl)benzenesulfonamide (7.45 g 31.9 mmol) in THF (200 mL). This was followed by the addition of NaH (60% wt, 1.91 g, 79.6 mmol). The mixture was stirred at 0° C. for 0.5 h. This was followed by the addition of the solution of TBSCl (7.19 g, 47.9 mmol) in THF (50 mL) dropwise. The resulting solution was stirred at RT overnight. The reaction was quenched with ice-water (100 mL); the resulting solution was extracted with EtOAc (3×200 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified with SiO₂-gel column and eluted with ethyl acetate/petroleum ether (1:5 to 1:2). This resulted 10 g (90%) of the title compound as a white solid. MS-ESI: 348.1 (M+1).

Step 5: N′-(tert-butyldimethylsilyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzenesulfonimidamide

Into a 1 L 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of PPh₃Cl₂ (19.2 g, 57.6 mmol) in CHCl₃ (100 mL). This was followed by the addition of DIEA (7.4 g, 57.6 mmol) dropwise with stirring at 0° C. After stirred at 0° C. for 10 min, to the above was added a solution of N′-(tert-butyldimethylsilyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzenesulfonimidamide (10 g, 28.8 mmol) in CHCl₃ (100 mL) dropwise with stirring at 0° C. The resulting solution was allowed to react for 30 min at 0° C. To the mixture was added a saturated solution of ammonia in DCM (500 mL) at 0° C. The resulting solution was stirred for 2 h at RT. The solids were filtered out, and the filtrate was dilute with 100 mL of water. The resulting solution was extracted with 3×200 mL of DCM and the combined organic layers were dried over anhydrous Na₂SO₄ concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:3). This resulted in 5 g (50%) of the title compound as a light yellow solid. MS-ESI: 347.2 (M+1).

TABLE 4 The Intermediates in the following Table were prepared using similar procedure as shown in Scheme 9 above for converting compound 27 to Intermediate 11 starting from the appropriate materials. Exact Intermediate Mass # Structure IUPAC Name [M + H]⁺ Intermediate 12

N′-(tert-butyldimethylsilyl)-4-(2- hydroxypropan-2-yl)-2- methylbenzenesulfonimidamide 343.2 Intermediate 13

N′-(tert-butyldimethylsilyl)-3-(2- hydroxypropan-2- yl)benzenesulfonimidamide 329.1 Intermediate 14

N′-(tert-butyldimethylsilyl)-4-(2- hydroxypropan-2-yl)-3- methylbenzenesulfonimidamide 343.2 Intermediate 15

N′-(tert-butyldimethylsilyl)-4-fluoro-3-(2- hydroxypropan-2- yl)benzenesulfonimidamide 347.2 Intermediate 16

N′-(tert-butyldimethylsilyl)-3-fluoro-5-(2- hydroxpropan-2- yl)benzenesulfonimidamide 347.2 Intermediate 17

N′-(tert-butyldimethylsilyl)-3-fluoro-4-(2- hydroxypropan-2-yl)benzenesulfonimidamide 347.2 Intermediate 18

N′-(tert-butyldimethylsilyl)-2-chloro-4-(2- hydroxypropan-2- yl)benzenesulfonimidamide 363.1

TABLE 5 The Intermediate in the following Table was prepared using similar procedure as shown in Scheme 9 above for converting compound 28 to Intermediate 11 starting from methyl 4- (chlorosulfonyl)benzoate. Exact Intermediate Mass # Structure IUPAC Name [M + H]⁺ Intermediate 19

N′-(tert-butyldimethylsilyl)-4-(2- hydroxypropan-2- yl)benzenesulfonimidamide 329.2

Intermediate 18

N′-(tert-butyldimethylsilyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide Step 1: 1-Isopropyl-3-nitro-1H-pyrazole

Into a 250-mL round-bottom flask was placed a solution of 3-nitro-1H-pyrazole (10 g, 88.4 mmol) in DMF (100 mL). This was followed by the addition of NaH (60% wt., 3.9 g, 97.5 mmol) in portions at 0° C. The resulting solution was stirred for 0.5 h at 0° C. This was followed by the addition of 2-bromopropane (14.1 g, 114.6 mmol) dropwise with stirring at 0° C. in 10 min. The resulting solution was stirred for 16 h at RT and then was quenched by the addition of 100 mL of water. The resulting solution was extracted with 3×100 mL of ethyl acetate. The organic layers were combined and dried over anhydrous Na₂SO₄, then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in 11.8 g (86%) of the title compound as yellow oil. MS-ESI: 156.1 (M+1).

Step 2: 3-Amino-1-(propan-2-yl)-1H-pyrazole

Into a 250-mL round-bottom flask was placed a solution of 1-isopropyl-3-nitro-1H-pyrazole (10.8 g, 69.6 mmol) in MeOH (100 mL). Then Pd/C (10% wt., 1.5 g) was added. The flask was evacuated and flushed three times with hydrogen. The mixture was stirred for 24 h at RT under an atmosphere of hydrogen. The solids were filtered out. The resulting filtrate was concentrated under vacuum. This resulted in 7.27 g (83%) of the title compound as yellow oil. MS-ESI: 126.1 (M+1).

Steps 3-4 used similar procedures for converting compound 27 to compound 29 shown in Scheme 9 to afford compound 50 from compound 48. MS-ESI: 188.0 (M−1).

Steps 5-6 were using the similar procedures for converting compound 30 to Intermediate 11 shown in Scheme 9 to afford Intermediate 18 from compound 50. MS-ESI: 303.2 (M+1).

TABLE 6 The Intermediate in the following Table was prepared using similar procedure as shown in Scheme 10 above for converting compound 48 to Intermediate 18 starting from the appropriate materials. Exact Intermediate Mass # Structure IUPAC Name [M + H]⁺ Intermediate 21

N′-(tert-butyldimethylsilyl)-4- (methylsulfonyl)benzenesulfonimidamide 349.1 Intermediate 22

N′-(tert-butyldimethylsilyl)-3- (methylsulfonyl)benzenesulfonimidamide 349.1

Intermediate 23

N′-(tert-butyldimethylsilyl)-4-((dimethylamino)methyl)benzenesulfonimidamide Step 1: 4-Nitrobenzoyl chloride

Into a 500-mL round-bottom flask was placed 4-nitrobenzoic acid (20 g, 120 mmol), DCM (200 mL), and DMF (0.2 mL). This was followed by the addition of oxalyl chloride (15 mL, 177.1 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 4 h at RT and then was concentrated under vacuum. This resulted in 22 g (crude) of the title compound as yellow oil. The crude product was used in the next step.

Step 2: N,N-dimethyl-4-nitrobenzamide

Into a 500-mL round-bottom flask was placed dimethylamine hydrochloride (6.5 g, 79.7 mmol), DCM (200 mL), and TEA (50 mL). This was followed by the addition of 4-nitrobenzoyl chloride (22 g, 119 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 6 h at RT and then was concentrated under vacuum. The resulting mixture was washed with 2×50 mL of water. The solids were collected by filtration. This resulted in 16 g (69% over two steps) of the title compound as a white solid. MS-ESI: 195.1 (M+1).

Step 3: 4-Amino-N,N-dimethylbenzamide

Into a 250-mL round-bottom flask was placed N,N-dimethyl-4-nitrobenzamide (16 g, 82.4 mmol), MeOH (100 mL). Then Pd/C (10% wt., 1 g) was added. The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 12 h at RT under an atmosphere of hydrogen. The solids were filtered out. The resulting filtrate was concentrated under vacuum. This resulted in 13 g (96%) of the title compound as a white solid. MS-ESI: 165.1 (M+1).

Steps 4-5 used similar procedures for converting compound 27 to compound 29 shown in Scheme 9 to afford compound 43 from compound 41. MS-ESI: 229.1 (M+1).

Step 6: 4-((Dimethylamino)methyl)benzenesulfonamide

Into a 100-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of N,N-dimethyl-4-sulfamoylbenzamide (1.8 g, 7.9 mmol) in THF (50 mL). This was followed by the addition of 9-BBN (5.8 g) in portions at 0° C. The resulting solution was stirred for 12 h at 70° C. and then was quenched by the addition of 20 mL of water/ice. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 200 mL of water and then the organic layer was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of DCM/MeOH (20:1 to 15:1). This resulted in 1 g (59%) of the title compound as a white solid. MS-ESI: 215.1 (M+1).

Steps 7-8 were using the similar procedures for converting compound 30 to Intermediate 11 shown in Scheme 9 to afford Intermediate 23 from compound 44. MS-ESI: 328.2 (M+1).

Intermediate 24

N′-(tert-butyldimethylsilyl)-3-((dimethylamino)methyl)benzenesulfonimidamide Step 1: 3-amino-N,N-dimethylbenzamide

Into a 1000-mL round-bottom flask was placed dimethylamine as a hydrochloride salt (16.3 g, 200 mmol) in DCM (500 mL), DIEA (25.83 mg, 200 mmol). To the above was added 3-aminobenzoic acid (13.7 g, 100 mmol), HATU (57 g, 150 mmol). The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 500 mL of NH₄Cl (aq.). The resulting solution was extracted with 3×500 ml of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column and eluted with a gradient of DCM/methanol (50:1 to 20:1). This resulted in 13.14 g (80%) of the title compound as a yellow solid. MS-ESI: 165.1 (M+1).

Steps 2-6 used the similar procedures for converting compound 41 to Intermediate 23 shown in Scheme 11 to afford Intermediate 24 from compound 47. MS-ESI: 328.2 (M+1).

Intermediate 25

N′-(tert-butyldimethylsilyl)-4-((dimethylamino)methyl)-2-fluorobenzenesulfonimidamide

Steps 1-5 used similar procedures for converting compound 38 to compound 43 shown in Scheme 11 to afford compound 57. MS-ESI: 247.0 (M+1).

Step 6: 4-((Dimethylamino)methyl)-2-fluorobenzenesulfonamide

Into a 1-L round-bottom flask was placed a solution of 3-fluoro-N,N-dimethyl-4-sulfamoylbenzamide (19.3 g, 78.4 mmol) in THF (200 mL). This was followed by the addition of LiAlH₄ (8.8 g, 231.9 mmol) in portions at 0° C. The resulting solution was stirred for 12 h at RT and then was quenched by the addition of 10 mL of water. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (6:1 to 8:1). This resulted in 7.0 g (38%) of the title compound as a white solid. MS-ESI: 233.1 (M+1).

Steps 7-8 used similar procedures for converting compound 44 to Intermediate 23 shown in Scheme 11 to afford Intermediate 25. MS-ESI: 346.2 (M+1).

Intermediate 26

N′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide Step 1: (2-Bromothiazol-4-yl)methanol

Into a 500-mL round-bottom flask was placed a solution of ethyl 2-bromothiazole-4-carboxylate (14 g, 59.3 mmol), EtOH (200 mL). This was followed by the addition of NaBH₄ (2.3 g, 60.5 mmol) in portions at 0° C. The resulting solution was stirred for 3 h at RT and then was quenched by the addition of 100 mL of water. The resulting solution was extracted with 2×200 mL of DCM. The organic layers were combined, dried over anhydrous Na₂SO₄ and then concentrated under vacuum. This resulted in 10.0 g (87%) of the title compound as colorless oil. MS-ESI: 195.9, 193.9 (M+1).

Step 2: 2-Bromothiazole-4-carbaldehyde

Into a 250-mL round-bottom flask was placed a solution of (2-bromothiazol-4-yl)methanol (10.0 g, 51.5 mmol) in DCM (100 mL). To the solution was added Dess-Martin reagent (24.0 g, 56.6 mmol). The resulting solution was stirred for 2 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:50 to 1:20). This resulted in 8.0 g (81%) of the title compound as yellow oil. MS-ESI: 193.9, 191.9 (M+1).

Step 3: 1-(2-Bromothiazol-4-yl)ethanol

Into a 250-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 2-bromothiazole-4-carbaldehyde (8 g, 41.7 mmol) in THF (100 mL). This was followed by the addition of MeMgBr (3 M in THF, 15 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at RT and then was quenched by the addition of 100 mL of NH₄Cl (sat.). The resulting solution was extracted with 3×100 mL of DCM and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:5). This resulted in 6.0 g (69%) of the title compound as brown oil. MS-ESI: 209.9, 207.9 (M+1).

Step 4: 2-Bromo-4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole

Into a 250-mL round-bottom flask was placed a solution of 1-(2-bromothiazol-4-yl)ethanol (6.0 g, 28.8 mmol) and 1H-imidazole (4.0 g, 58.8 mmol) in DMF (50 mL). To the solution was added TBDPSCl (8.7 g, 31.6 mmol). The resulting solution was stirred for 12 h at RT and then was diluted with 100 mL of water. The resulting solution was extracted with 3×100 mL of DCM and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:100 to 1:50). This resulted in 10.0 g (78%) of the title compound as light yellow oil. MS-ESI: 448.1, 446.1 (M+1).

Step 5: 4-(1-(Tert-butyldiphenylsilyloxy)ethyl)thiazole-2-sulfonyl chloride

Into a 250-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 2-bromo-4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole (10.0 g, 22.4 mmol) in THF (100 mL). This was followed by the addition of n-BuLi (2.5 M in THF, 11 mL) dropwise with stirring at −78° C. The resulting solution was stirred for 30 min at −78° C. To the above SO₂ gas was introduced. The reaction was warmed to RT and stirred for 30 min and then was concentrated under vacuum. The residue was dissolved in DCM (100 mL) and then NCS (3.6 g, 26.9 mmol) was added. The resulting solution was stirred for 30 min at RT and then was concentrated under vacuum. This resulted in 8.0 g (crude, 77%) of the title compound as a white solid. The crude product was used in the next step.

Step 6: N-tert-butyl-4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-2-sulfonamide

Into a 100-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of 4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-2-sulfonyl chloride (8.0 g, 17.2 mmol) in DCM (50 mL). To the solution were added TEA (3.5 g, 34.6 mmol) and 2-methylpropan-2-amine (1.9 g, 26.0 mmol). The resulting solution was stirred for 2 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:15 to 1:5). This resulted in 8.0 g (71%, 2 steps) of the title compound as brown oil. MS-ESI: 503.2 (M+1).

Step 7: N-tert-butyl-4-(1-hydroxyethyl)thiazole-2-sulfonamide

Into a 250-mL round-bottom flask was placed a solution of N-tert-butyl-4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-2-sulfonamide (8.0 g, 15.9 mmol) in THF (100 mL). To the solution was added TBAF (9.6 g, 292.5 mmol). The resulting solution was stirred for 2 h at RT and then was diluted with 100 mL of water. The resulting solution was extracted with 3×100 mL of DCM and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:3). This resulted in 4.0 g (95%) of the title compound as light yellow oil. MS-ESI: 265.1 (M+1).

Step 8: 4-Acetyl-N-tert-butylthiazole-2-sulfonamide

Into a 100-mL round-bottom flask was placed a solution of N-tert-butyl-4-(1-hydroxyethyl)thiazole-2-sulfonamide (4.0 g, 15.1 mmol) in DCM (50 mL). To the solution was added Dess-Martin reagent (7.1 g, 16.6 mmol). The resulting solution was stirred for 2 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:3). This resulted in 3.5 g (88%) of the title compound as light yellow oil. MS-ESI: 363.0 (M+1).

Step 9: 4-Acetylthiazole-2-sulfonamide

Into a 100-mL round-bottom flask was placed a solution of 4-acetyl-N-tert-butylthiazole-2-sulfonamide (3.5 g, 13.3 mmol) in DCM (5 mL). To the solution was added TFA (20 mL). The resulting solution was stirred for 14 h at 40° C. and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:3). This resulted in 2.5 g (91%) of the title compound as a gray solid. MS-ESI: 207.0 (M+1).

Steps 10-12 used similar procedures for converting compound 29 to Intermediate 11 shown in Scheme 9 to afford Intermediate 26 from compound 69. MS-ESI: 336.1 (M+1).

Intermediate 27

N′-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide Step 1: 1-(Thiazol-2-yl)ethanol

Into a 500-mL round-bottom flask was placed 1-(thiazol-2-yl)ethanone (20 g, 157 mmol), EtOH (200 mL). This was followed by the addition of NaBH₄ (3 g, 81.3 mmol) in portions at 0° C. The resulting solution was stirred for 2 h at RT and then was quenched by the addition of 10 mL of NH₄Cl (sat.). The resulting solution was diluted with 200 mL of water and extracted with 2×200 mL of DCM. The organic layers were combined and dried over anhydrous Na₂SO₄, then concentrated under vacuum. This resulted in 20 g (98%) of the title compound as light yellow oil. MS-ESI: 130.0 (M+1).

Step 2: 2-(1-(Tert-butyldiphenylsilyloxy)ethyl)thiazole

Into a 500-mL round-bottom flask was placed 1-(thiazol-2-yl)ethanol (20 g, 154.8 mmol), DMF (150 mL), 1H-imidazole (20.5 g, 301 mmol). This was followed by the addition of TBDPSCl (46 g, 167 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at RT and then was diluted with 300 mL of water. The resulting solution was extracted with 3×200 mL of DCM. The organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:100 to 1:80). This resulted in 55 g (97%) of the title compound as colorless oil. MS-ESI: 368.1 (M+1).

Step 3: 2-(1-(Tert-butyldiphenylsilyloxy)ethyl)thiazole-5-sulfonyl chloride

Into a 500-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole (30 g, 81.6 mmol) in THF (200 mL). This was followed by the addition of n-BuLi (2.5 M in THF, 35.2 mL) dropwise with stirring at −78° C. The resulting solution was stirred for 0.5 h at −78° C. and then SO₂ was introduced into the above reaction mixture. The reaction was slowly warmed to RT and then NCS (12.8 g, 95.86 mmol) was added. The resulting solution was stirred for 1 h at RT. The solids were filtered out. The resulting filtrate was concentrated under vacuum. This resulted in 30 g (crude, 79%) of the title compound as brown oil. The crude product was used in the next step.

Step 4: N-tert-butyl-2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-5-sulfonamide

Into a 500-mL round-bottom flask was placed 2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-5-sulfonyl chloride (crude, 30 g, 64.37 mmol), DCM (200 mL), TEA (13 g, 128.47 mmol). This was followed by the addition of 2-methylpropan-2-amine (5.6 g, 76.6 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:30 to 1:20). This resulted in 25 g (61% over two steps) of the title compound as brown oil. MS-ESI: 503.2 (M+1).

Step 5: N-tert-butyl-2-(1-hydroxyethyl)thiazole-5-sulfonamide

Into a 500-mL round-bottom flask was placed N-tert-butyl-2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-5-sulfonamide (25 g, 49.7 mmol), THF (200 mL), TBAF (30 g, 99.67 mmol). The resulting solution was stirred for 2 h at RT and then was diluted with 200 mL of water. The resulting solution was extracted with 3×200 mL of DCM. The organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:20 to 1:10). This resulted in 12 g (91%) of the title compound as light yellow oil. MS-ESI: 265.1 (M+1).

Step 6: 2-Acetyl-N-tert-butylthiazole-5-sulfonamide

Into a 500-mL round-bottom flask was placed N-tert-butyl-2-(1-hydroxyethyl)thiazole-5-sulfonamide (12 g, 45.4 mmol), DCM (200 mL). To this solution was added Dess-Martin reagent (20 g, 47.2 mmol) in portions at RT. The resulting solution was stirred for 2 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:20 to 1:10). This resulted in 9 g (76%) of the title compound as a light yellow solid. MS-ESI: 263.0 (M+1).

Step 7: 2-Acetylthiazole-5-sulfonamide

Into a 100-mL round-bottom flask was placed 2-acetyl-N-tert-butylthiazole-5-sulfonamide (7 g, 26.7 mmol), TFA (20 mL). The resulting solution was stirred for 14 h at 70° C. and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in 5 g (91%) of the title compound as a yellow solid. MS-ESI: 207.0 (M+1).

Step 8: 2-(2-Hydroxypropan-2-yl)thiazole-5-sulfonamide

Into a 500-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed 2-acetylthiazole-5-sulfonamide (5 g, 24.3 mmol), THF (100 mL). This was followed by the addition of MeMgBr (3 M in THF, 8.1 mL, 24.3 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 14 h at RT and then was quenched by the addition of 100 mL of NH₄Cl (sat.). The resulting solution was extracted with 2×150 mL of DCM. The organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in 2.9 g (54%) of the title compound as a light yellow solid. MS-ESI: 223.0 (M+1).

Steps 9-10 used similar procedures for converting compound 14 to Intermediate 1 shown in Scheme 6 to afford Intermediate 27 from compound 80. MS-ESI: 336.1 (M+1).

Intermediate 27

N′-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide Step 1: 2-(2-Methyl-1,3-dioxolan-2-yl)thiazole

Into a 500-mL round-bottom flask was placed a solution of 1-(thiazol-2-yl)ethanone (20 g, 157.0 mmol) in toluene (300 mL) and ethane-1,2-diol (19.5 g, 314 mmol). To the solution was added TsOH (2.7 g, 15.7 mmol). The resulting solution was refluxed overnight and water was separated from the solution during the reflux. The resulting solution was diluted with 200 mL of water and extracted with 2×100 mL of ethyl acetate. The organic layers were combined, dried over anhydrous Na₂SO₄, and then concentrated under vacuum. This resulted in 26.6 g (99%) of the title compound as light yellow oil. MS-ESI: 172.0 (M+1).

Step 2: 2-(2-Methyl-1,3-dioxolan-2-yl)thiazole-5-sulfonamide

Into a 500-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 2-(2-methyl-1,3-dioxolan-2-yl)thiazole (14 g, 81.6 mmol) in THF (200 mL). This was followed by the addition of n-BuLi (2.5 M in THF, 35.2 mL, 88.0 mmol) dropwise with stirring at −78° C. The resulting solution was stirred for 0.5 h at −78° C. and then SO₂ was introduced into the above reaction mixture. The reaction was slowly warmed to RT and then NCS (12.8 g, 95.86 mmol) was added. The resulting solution was stirred for 1 h at RT. The solids were filtered out. The resulting filtrate was concentrated under vacuum and then was diluted in DCM (160 mL). To the above was added a saturated solution of ammonia in DCM (300 mL). The resulting solution was stirred for 3 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:20 to 1:5). This resulted in 12.5 g (61%) of the title compound as a yellow solid. MS-ESI: 251.0 (M+1).

Step 3: 2-Acetylthiazole-5-sulfonamide

Into a 250-mL round-bottom flask was placed a solution of 2-(2-methyl-1,3-dioxolan-2-yl)thiazole-5-sulfonamide (12.5 g, 50.0 mmol) in THF (125 mL). To the above was added aq. HCl (4 N, 50.0 mL). The resulting solution was stirred for 6 h at 70° C. The resulting solution was diluted with 100 mL of water and extracted with 2×200 mL of ethyl acetate. The organic layers were combined, dried over anhydrous Na₂SO₄, then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:2 to 1:1). This resulted in 9.3 g (90%) of the title compound as a yellow solid. MS-ESI: 207.0 (M+1).

Steps 4-6 used the same procedures for converting compound 19 to Intermediate 2 shown in Scheme 7B to afford Intermediate 27 from compound 84. MS-ESI: 336.1 (M+1).

Intermediate 28

N′-(tert-butoxycarbonyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide Step 1: 2-(Thiazol-2-yl)propan-2-ol

Into a 10-L 4-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 1-(thiazol-2-yl)ethanone (200 g, 1.6 mol) in THF (4 L). This was followed by the addition of MeMgBr (3 M in THF, 942 mL) dropwise with stirring at 0° C. The mixture was stirred at 0° C. for 2 h. After warmed the mixture to RT, the solution was stirred for an additional 16 h. Then the reaction was quenched by the addition of 3 L of NH₄Cl (sat.). The resulting solution was extracted with 3×1 L of ethyl acetate. The organic layers were combined, dried over anhydrous Na₂SO₄, then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:3 to 1:1). This resulted in 210 g (93%) of the title compound as a brown oil. MS-ESI: 144.0 (M+1).

Step 2: Lithium 2-(2-hydroxypropan-2-yl)thiazole-5-sulfinate

Into a 10-L 4-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 2-(thiazol-2-yl)propan-2-ol (50 g, 349.0 mmol) in THF (1.5 L). This was followed by the addition of n-BuLi (2.5 M in hexane, 350 mL) dropwise with stirring at −78° C. The mixture was stirred at −78° C. for 1 h. Then SO₂ was bubbled into the mixture for 15 min below −30° C. The mixture was stirred for an additional 1 h at RT and then was concentrated under vacuum. This resulted in 87 g (crude) of the title compound as a light yellow solid. The crude product was used directly in the next step.

Step 3: Methyl 2-(2-hydroxypropan-2-yl)thiazole-5-sulfinate

Into a 2-L 3-necked round-bottom flask, lithium 2-(2-hydroxypropan-2-yl)thiazole-5-sulfinate (87 g, crude) was dissolved in anhydrous MeOH (500 mL). Then SOCl₂ (43 g, 360 mmol) was added to the mixture dropwise with stirring at 0° C. The mixture was stirred overnight at RT and then was concentrated under vacuum. The residue was diluted with 500 mL of ethyl acetate. The resulting solution was washed with 2×200 mL of water and 2×200 mL of brine. The solution was dried over anhydrous Na₂SO₄, then concentrated under vacuum. This resulted in 72 g (crude) of the title compound as light yellow oil. The crude product was used directly in the next step.

Step 4: 2-(2-Hydroxypropan-2-yl)thiazole-5-sulfinamide

Into a 10-L 4-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of methyl 2-(2-hydroxypropan-2-yl)thiazole-5-sulfinate (72 g, 326 mmol) in THF (500 mL). Then to the above NH₃ (0.5 M in THF, 2.0 L) was added. After cooling to −78° C., LiHMDS (1 M in THF, 2.0 L) was added to the mixture dropwise with stirring. Then the mixture was stirred at −78° C. for 2 h. The reaction was quenched by the addition of 500 mL of NH₄Cl (sat.). The resulting solution was extracted with 3×300 mL of ethyl acetate. The organic layers were combined, dried over anhydrous Na₂SO₄, then concentrated under vacuum. This resulted in 32 g (crude) of the title compound as brown oil. The crude product was used directly in the next step.

Step 5: Tert-butyl 2-(2-hydroxypropan-2-yl)thiazol-5-ylsulfinylcarbamate

Into a 1-L 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 2-(2-hydroxypropan-2-yl)thiazole-5-sulfinamide (32 g, crude) in THF (300 mL). This was followed by the addition of LDA (2 M in THF, 116 mL) dropwise with string at 0° C. The mixture was stirred at 0° C. for 1 h, then (Boc)₂O (33.8 g, 155 mmol) was added in portions at 0° C. The mixture was warmed to RT and stirred for an additional 2 h. The reaction was quenched with 200 mL of ice-water (200 mL), and the pH value of the solution was adjusted to 6 with HCOOH. The resulting solution was extracted with 3×200 mL of ethyl acetate. The organic layers were combined, dried over anhydrous Na₂SO₄, then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:2 to 1:1). This resulted in 19 g (18%, 4 steps) of the title compound as a white solid.

Step 6: N-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 1-L 3-necked round-bottom flask purged with and maintained under nitrogen, tert-butyl 2-(2-hydroxypropan-2-yl)thiazol-5-ylsulfinylcarbamate (19 g, 62 mmol) was dissolved in fresh distilled ACN (200 mL). Then to the above solution was added NCS (9.8 g, 74 mmol) in portions. The mixture was stirred for 1 h at RT and then NH₃ was bubbled in the mixture for 15 min. The mixture was stirred at RT for 2 h and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:2 to 1:1). This resulted in 13 g (65%) of the title compound as a white solid.

Intermediate 29

4-(2-Hydroxypropan-2-yl)-N′-methylthiophene-2-sulfonimidamide

Step 1 used the procedures for converting compound 15 to Intermediate 1 shown in Scheme 6 to afford compound 93 by substituting ammonia with methylamine. MS-ESI: 349.1 (M+1).

Step 2: 4-(2-Hydroxypropan-2-yl)-N′-methylthiophene-2-sulfonimidamide

Into a 25-mL round-bottom flask purged with under nitrogen was placed a solution of N′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-N-methylthiophene-2-sulfonimidamide (500 mg, 1.43 mmol) in DCM (10 mL). To the solution was added HF/Py (70% wt., 200 mg). The resulting solution was stirred for 2 h at RT. The pH value of the solution was adjusted to 8 with aq. Na₂CO₃ (5% wt.). The resulting solution was extracted with 3×10 mL of ethyl acetate. The organic layers were combined, dried over anhydrous Na₂SO₄, then concentrated under vacuum. This resulted in 300 mg (89%) of the title compound as brown oil. MS-ESI: 235.0 (M+1).

Schemes for the preparation of Isocyanate Intermediates 30-58:

Schemes below illustrate the synthesis of isocyanates.

Intermediate 30

4-Fluoro-2,6-diisopropylbenzenamine Step 1: 4-Fluoro-2,6-bis(prop-1-en-2-yl)aniline

Into a 500-mL round-bottom flask purged with and maintained under nitrogen was placed 2,6-dibromo-4-fluoroaniline (15 g, 55.8 mmol), dioxane (150 mL), water (15 mL), Cs₂CO₃ (55 g, 169 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (25 g, 149 mmol), and Pd(dppf)Cl₂ (4 g, 5.47 mmol). The resulting solution was stirred for 15 h at 100° C. and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1: 10 to 1:8). This resulted in 9.2 g (86%) of the title compound as brown oil. MS-ESI: 192.1 (M+1).

Step 2: 4-Fluoro-2,6-bis(propan-2-yl)aniline

Into a 500-mL round-bottom flask was placed 4-fluoro-2,6-bis(prop-1-en-2-yl)aniline (9.2 g, 48.1 mmol), and MeOH (200 mL). Then Pd/C (10% wt., 900 mg) was added. The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 12 h at RT under an atmosphere of hydrogen. The solids were filtered out. The resulting filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:8). This resulted in 7.2 g (77%) of the title compound as brown oil. MS-ESI: 196.1 (M+1).

Intermediate 31

4-Amino-2-fluoro-3,5-diisopropylbenzonitrile Step 1: 4-Amino-3,5-dibromo-2-fluorobenzonitrile

Into a 1-L round-bottom flask was placed 4-amino-2-fluorobenzonitrile (25 g, 184 mmol), ACN (500 mL), and NBS (81.7 g, 459 mmol). The resulting solution was stirred overnight at 75° C. and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:100 to 1:98). This resulted in 50 g (93%) of the title compound as brown oil. MS-ESI: 294.9/292.9/296.9 (M+1).

Steps 2-3 used similar procedures for converting compound 94 to Intermediate 30 shown in Scheme 18 to afford Intermediate 31 from compound 97. MS-ESI: 221.1 (M+1).

Intermediate 32

4-(Difluoromethoxy)-2,6-diisopropylbenzenamine Step 1: 2,6-Dibromo-4-(difluoromethoxy)benzenamine

Into a 100-mL round-bottom flask was placed 4-(difluoromethoxy)benzenamine (3 g, 18.9 mmol), ACN (30 mL), and NBS (7.7 g, 43.3 mmol). The resulting solution was stirred overnight at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:30 to 1:20). This resulted in 2.9 g (48%) of the title compound as brown oil. MS-ESI: 317.9/315.9/319.9 (M+1).

Steps 2-3 used similar procedures for converting compound 94 to Intermediate 30 shown in Scheme 18 to afford Intermediate 32 from compound 100″. MS-ESI: 244.1 (M+1).

Intermediate 33

4-(Difluoromethoxy)-2-ethyl-6-isopropylbenzenamine Step 1: 2-Bromo-4-(difluoromethoxy)benzenamine

Into a 250-mL round-bottom flask purged with and maintained under nitrogen was placed 4-(difluoromethoxy)benzenamine (10 g, 62.8 mmol), ACN (100 mL), and NBS (5.59 g, 31.4 mmol). The resulting solution was stirred for 1 h RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:20 to 1:10). This resulted in 7.9 g (53%) of the title compound as red oil. MS-ESI: 238.0/240.0 (M+1).

Step 2: 4-(Difluoromethoxy)-2-(prop-1-en-2-yl)benzenamine

Into a 250-mL round-bottom flask purged with and maintained under nitrogen was placed 2-bromo-4-(difluoromethoxy)benzenamine (7.9 g, 33.2 mmol), dioxane (100 mL), water (10 mL), Cs₂CO₃ (32.46 g, 99.63 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (8.36 g, 49.8 mmol), and Pd(dppf)Cl₂ (1.21 g, 1.65 mmol). The resulting solution was stirred overnight at 90° C. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:30 to 1:20). This resulted in 5.3 g (80%) of the title compound as a yellow solid. MS-ESI: 200.1 (M+1).

Step 3: 4-(Difluoromethoxy)-2-isopropylbenzenamine

Into a 250-mL round-bottom flask was placed 4-(difluoromethoxy)-2-(prop-1-en-2-yl)benzenamine (5.3 g, 26.6 mmol) in MeOH (100 mL). Then Pd/C (10% wt., 500 mg) was added. The flask was evacuated and filled three times with hydrogen. The resulting solution was stirred for 3 h at RT under hydrogen. The solids were filtered out. The resulting filtrate was concentrated under vacuum. This resulted in 5.15 g (96%) of the title compound as red oil. MS-ESI: 202.1 (M+1).

Step 4: 2-Bromo-4-(difluoromethoxy)-6-isopropylbenzenamine

Into a 500-mL round-bottom flask was placed 4-(difluoromethoxy)-2-isopropylbenzenamine (5.15 g, 25.6 mmol), CHCl₃ (200 mL), Fe turnings (500 mg), and Br₂ (4.45 g, 27.9 mmol). The resulting mixture was stirred overnight at 70° C. and then was quenched by the addition of 200 mL of water. The resulting solution was extracted with 3×100 mL of DCM and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:30 to 1:20). This resulted in 6.98 g (97%) of the title compound as dark red oil. MS-ESI: 280.0/282.0 (M+1).

Step 5: 4-(Difluoromethoxy)-2-isopropyl-6-vinylbenzenamine

Into a 250-mL round-bottom flask purged with and maintained under nitrogen was placed 2-bromo-4-(difluoromethoxy)-6-isopropylbenzenamine (3 g, 10.7 mmol), dioxane (100 mL), water (10 mL), Cs₂CO₃ (10.47 g, 32.13 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.47 g, 16.0 mmol), and Pd(dppf)Cl₂ (784 mg, 1.07 mmol). The resulting solution was stirred overnight at 90° C. and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:30 to 1:20). This resulted in 2.3 g (94%) of the title compound as dark green oil. MS-ESI: 228.1 (M+1).

Step 6: 4-(Difluoromethoxy)-2-ethyl-6-isopropylbenzenamine

Into a 250-mL round-bottom flask was placed 4-(difluoromethoxy)-2-isopropyl-6-vinylbenzenamine (2.3 g, 10.1 mmol), MeOH (100 mL). Then Pd/C (10% wt., 200 mg) was added. The flask was evacuated and filled three times with hydrogen. The resulting solution was stirred overnight at RT under hydrogen. The solids were filtered out. The filtrate was concentrated under vacuum. This resulted in 2.2 g (95%) of the title compound as red oil. MS-ESI: 230.1 (M+1).

TABLE 7 The Intermediate 34 in the following Table was prepared from compound 105” using similar procedure as shown in Scheme 21 above for converting compound 105” to 106”. Exact Intermediate Mass # Structure IUPAC Name [M + H]⁺ Intermediate 34

2-Cyclopropyl-4-(difluoromethoxy)-6- isopropylbenzenamine 242.1

Intermediate 35

4-Amino-5-cyclopropyl-2-fluoro-3-isopropylbenzonitrile Step 1: 4-Amino-5-bromo-2-fluorobenzonitrile

Into a 250-mL round-bottom flask was placed a solution of 4-amino-2-fluorobenzonitrile (9 g, 66.1 mmol) in ACN (120 mL). Then NBS (12.4 g, 69.7 mmol) was added. The resulting solution was stirred overnight at 80° C. and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:20 to 1:10). This resulted in 10.9 g (77%) of the title compound as a yellow solid. MS-ESI: 215.0/217.0 (M+1). ¹H NMR (300 MHz, DMSO-d₆) δ 7.89 (d, J=6.0 Hz, 1H), 6.69 (br s, 2H), 6.63 (d, J=12.0 Hz, 1H).

Step 2: 4-Amino-5-cyclopropyl-2-fluorobenzonitrile

Into a 250-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of 4-amino-5-bromo-2-fluorobenzonitrile (6.37 g, 29.6 mmol) in dioxane (70 mL) and water (10 mL). To the solution were added Cs₂CO₃ (9.7 g, 29.8 mmol), cyclopropylboronic acid (3.8 g, 44.2 mmol) and Pd(dppf)Cl₂ (1.08 g, 1.48 mmol). The resulting solution was stirred overnight at 90° C. and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:5). This resulted in 5.03 g (96%) of the title compound as a yellow solid. MS-ESI: 177.1 (M+1).

Step 3: 4-Amino-3-bromo-5-cyclopropyl-2-fluorobenzonitrile

Into a 250-mL round-bottom flask was placed a solution of 4-amino-5-cyclopropyl-2-fluorobenzonitrile (5.03 g, 28.7 mmol) in ACN (50 mL). To the solution was added NBS (5.6 g, 31.5 mmol). The resulting solution was stirred overnight at 80° C. and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:5). This resulted in 6.972 g (96%) of the title compound as a yellow solid. MS-ESI: 255.0/257.0 (M+1).

Step 4: 4-Amino-5-cyclopropyl-2-fluoro-3-(prop-1-en-2-yl)benzonitrile

Into a 250-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of 4-amino-3-bromo-5-cyclopropyl-2-fluorobenzonitrile (6.972 g, 27.33 mmol) in dioxane (120 mL) and water (20 mL). To the solution were added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (6.9 g, 41.00 mmol), Cs₂CO₃ (13.4 g, 41.00 mmol) and Pd(dppf)Cl₂ (0.4 g, 0.55 mmol). The resulting solution was stirred overnight at 80° C. and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:5). This resulted in 4.73 g (80%) of the title compound as a yellow solid. MS-ESI: 217.1 (M+1).

Step 5: 4-Amino-5-cyclopropyl-2-fluoro-3-isopropylbenzonitrile

Into a 250-mL round-bottom flask was placed a solution of 4-amino-5-cyclopropyl-2-fluoro-3-(prop-1-en-2-yl)benzonitrile (4.73 g, 21.97 mmol), MeOH (100 mL). To the solution was added AcOH (0.5 mL). Then Pd/C (10% wt., 500 mg) was added. The flask was evacuated and filled three times with hydrogen. The resulting solution was stirred for 4 h at 40° C. under an atmosphere of hydrogen. The solids were filtered out. The filtrate was concentrated under vacuum. This resulted in 4.71 g (99%) of the title compound as a light yellow solid. MS-ESI: 219.1 (M+1).

Intermediate 36

8-Fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine Step 1: 3-Chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one

Into a 3-L round-bottom flask was placed a solution of AlCl₃ (111 g, 834 mmol) in DCM (1200 mL). This was followed by the addition of a solution of 2,3-dihydro-1H-indene (90 g, 762 mmol) and 3-chloropropanoyl chloride (96.3 g, 759 mmol) in DCM (300 mL) dropwise with stirring at −10° C. in 30 min. The resulting solution was stirred for 16 h at RT. Then the reaction mixture was added dropwise to cold HCl (3 N, 1200 mL) over 45 min at −10° C. The resulting solution was extracted with 3×600 mL of DCM and the organic layers were combined, dried over anhydrous Na₂SO₄, then concentrated under vacuum. This resulted in 160.5 g (crude) of the title compound as a yellow solid. The crude product was used in the next step.

Step 2: 1,2,3,5,6,7-Hexahydro-s-indacen-1-one

Into a 1-L round-bottom flask was placed a solution of 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (160.5 g, 759 mmol) in conc. H₂SO₄ (900 mL). The resulting solution was stirred for 16 h at 55° C. and then was quenched by adding the reaction mixture carefully to 4500 mL of water/ice. The solids were collected by filtration and dried over infrared lamp for 24 h. The crude mixture was purified by chromatography and eluted with ethyl acetate/petroleum ether (1:100). This resulted in 10 g (7.6%) of 1,6,7,8-tetrahydro-as-indacen-3(2H)-one (compound 113″a) and 112.2 g (85%) of the title compound (compound 113″) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.44 (s, 1H), 7.39 (s, 1H), 3.13-2.79 (m, 8H), 2.70-2.55 (m, 2H), 2.20-1.90 (m, 2H). ¹H NMR (400 MHz, DMSO-d₆) δ 7.49 (d, J=7.7 Hz, 1H), 7.31 (d, J=7.7 Hz, 1H), 3.19-2.98 (m, 4H), 2.93-2.80 (m, 3H), 2.68-2.54 (m, 2H), 2.15-1.95 (m, 2H).

Step 3: 4-nitro-2,3,6,7-tetrahydro-s-indacen-1(5H)-one (114) (Major) and 8-nitro-2,3,6,7-tetrahydro-s-indacen-1(5H)-one (115) (Minor)

Into a 1-L round-bottom flask was placed a solution of 1,2,3,5,6,7-hexahydro-s-indacen-1-one (80 g, 464.5 mmol) in H₂SO₄ (500 mL). Then HNO₃ (58.5 g, 929 mmol) was added dropwise over 1 h at 0° C. The resulting solution was stirred for 1 hr at 0° C. The reaction mixture was slowly added to a mixture of water/ice (1000 mL) and DCM (500 mL) with ice bath cooling. The organic layer was collected, dried over Na₂SO₄ and concentrated under vacuum. This resulted in 90 g (90%) of the mixture of 4-nitro-2,3,6,7-hexahydro-s-indacen-1-one and 8-nitro-2,3,6,7-tetrahydro-s-indacen-1(5H)-one as a yellow solid.

Step 4: 1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Into a 1-L round-bottom flask was placed a solution of the mixture of 4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one and 8-nitro-2,3,6,7-tetrahydro-s-indacen-1(5H)-one (21.7 g, 100 mmol) in MeOH (300 mL). To the solution was added MSA (11.5 g, 120 mmol). Then Pd(OH)₂/C (20% wt, 5.5 g) was added. The flask was evacuated and filled three times with hydrogen. The resulting mixture was stirred for 16 h at RT under hydrogen (50 psi). The solids were filtered out and washed with methanol. The methanol filtrate and wash was diluted with water (500 mL) and the pH was adjusted to 10.6 with 2N NaOH. The resulting slurry was filtered and the crude solids were recrystallized from methanol/water (9:1) with heating. This resulted in 13.7 g (79%) of the title compound as an off-white solid.

Step 5: 8-Nitro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Into a 500-mL round-bottom flask was placed 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (8 g, 46.2 mmol), EtOH (200 mL), and 2,3,5,6-tetrabromo-4-methyl-4-nitrocyclohexa-2,5-dienone (21.6 g, 46.1 mmol). The resulting solution was stirred for 12 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:50 to 1:30). This resulted in 5 g (50%) of the title compound as a yellow solid. MS-ESI: 219.1 (M+1).

Step 6: 4-Fluoro-8-nitro-1,2,3,5,6,7-hexahydro-s-indacene

Into a 100-mL round-bottom flask was placed 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (5 g, 22.9 mmol) and HF/Py (70% wt., 20 mL). This was followed by the addition of 3-methylbutyl nitrite (3 g, 25.6 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at RT and then was diluted with 50 mL of water. The resulting solution was extracted with 3×50 mL of DCM. The organic layers were combined and dried over anhydrous Na₂SO₄, then concentrated under vacuum. This resulted in 4 g (crude, 79%) of the title compound as brown oil.

Step 7: 8-Fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Into a 100-mL round-bottom flask was placed 4-fluoro-8-nitro-1,2,3,5,6,7-hexahydro-s-indacene (4 g, 18.1 mmol) in MeOH (50 mL). Then Pd/C (10% wt., 0.5 g) was added. The flask was evacuated and filled three times with hydrogen. The resulting mixture was stirred for 12 h at RT under an atmosphere of hydrogen. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:10 to 1:5). This resulted in 2 g (46%, 2 steps) of the title compound as a white solid. MS-ESI: 192.1 (M+1).

Intermediate 37

1-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-amine Step 1: 4-nitro-2,3,6,7-tetrahydro-s-indacen-1(5H)-one

Into a 1-L round-bottom flask was placed a solution of 1,2,3,5,6,7-hexahydro-s-indacen-1-one (40 g, 232 mmol) in H₂SO₄ (250 mL). Then HNO₃ (29 g, 464 mmol) was added dropwise over 1 h at 0° C. The resulting solution was stirred for 1 hr at 0° C. The reaction mixture was slowly added to a mixture of water/ice (500 mL) and DCM (250 mL) with ice bath cooling. The organic layer was collected, dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was purified by silica gel column with a gradient of ethyl acetate and petroleum ether (1:50 to 1:1). This resulted in minor product 5 g (10%) of the title compound and major product 30 g (60%) of 8-nitro-2,3,6,7-tetrahydro-s-indacen-1(5H)-one both as a yellow solid.

Step 2: 1-methylene-4-nitro-1,2,3,5,6,7-hexahydro-s-indacene

Into a 250-mL round-bottom flask was placed a solution of methyltriphenylphosphanium bromide (16.4 g, 46.04 mmol) and t-BuOK (5.2 g, 46.0 mmol) in THF (150 mL) at 0° C. The resulting solution was stirred for 30 min at 0° C. Then the solution of 4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (5 g, 23.0 mmol) in THF (10 mL) was added dropwise to the reaction mixture at 0° C. The resulting solution was stirred overnight at RT. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 2.6 g (52%) of the title compound as a green solid.

Step 3: 1-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Into a 100-mL round-bottom flask was placed a solution of 1-methylidene-4-nitro-1,2,3,5,6,7-hexahydro-s-indacene (2.6 g, 12.1 mmol) in MeOH (20 mL), Pd/C (10% wt, 300 mg) was added. The flask was evacuated and filled three times with hydrogen. then H₂ (g) was introduced in with a balloon. The resulting solution was stirred for 2 h at RT. The Pd/C catalyst was filtered out. The filtrate was concentrated. This resulted in 2 g of the title compound as red oil.

TABLE 8 Intermediate 38 in the following Table was prepared from Compound 114” using similar procedure as shown in Scheme 24 above for converting compound 115” to intermediate 37. Exact Intermediate Mass # Structure IUPAC Name [M + H]⁺ Intermediate 38

3-methyl-1,2,3,5,6,7-hexahydro-s-indacen- 4-amine 188.1

Intermediate 39

8-Chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine Step 1: 8-Chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Into a 50-mL round-bottom flask was placed a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (1.73 g, 9.99 mmol) in DMF (10 mL). To the solution was added NCS (1.47 g, 11.0 mmol). The resulting solution was stirred overnight at RT and then was diluted with 30 mL of DCM. The resulting mixture was washed with 3×10 mL of water and the organic layer was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:20 to 1:10). This resulted in 1.88 g (91%) of the title compound as a yellow solid. MS-ESI: 208.1/210.1 (M+1).

Intermediate 40

8-Amino-1,2,3,5,6,7-hexahydro-s-indacene-4-carbonitrile Step 1: 8-Bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Into a 100-mL round-bottom flask was placed a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (2.6 g, 15.0 mmol) in DMF (30 mL). To the solution was added NBS (2.9 g, 16.3 mmol). The resulting solution was stirred for 12 h at RT and then was diluted with 80 mL of ethyl acetate. The resulting mixture was washed with 3×20 mL of water and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:30 to 1:20). This resulted in 3.0 g (79%) of the title compound as a brown solid. MS-ESI: 252.0, 254.0 (M+1).

Step 2: 8-Amino-1,2,3,5,6,7-hexahydro-s-indacene-4-carbonitrile

Into a 50-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of 8-bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (725 mg, 2.88 mmol) in DMF (10 mL). To the solution were added t-BuOK (330 mg, 2.90 mmol), CuCN (386 mg, 4.32 mmol), and Pd(dppf)Cl₂ (424 mg, 0.58 mmol). The resulting solution was stirred for 12 h at 120° C. and then was diluted with 20 mL of water. The resulting solution was extracted with 3×20 mL ethyl acetate. The organic layers were combined, dried over anhydrous Na₂SO₄, then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:60 to 1:40). This resulted in 192 mg (34%) of the title compound as a yellow solid. MS-ESI: 199.1 (M+1).

Intermediate 41

4-Amino-3,5-diisopropylbenzonitrile Step 1: 4-Amino-3,5-diisopropylbenzonitrile

Into a 100-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of 4-bromo-2,6-diisopropylbenzenamine (5.1 g, 19.9 mmol) in DMF (30 mL). To the solution were added Zn(CN)₂ (2.80 g, 23.9 mmol), Pd(dppf)Cl₂ (732 mg, 1.00 mmol) and t-BuOK (3.36 g, 29.9 mmol). The resulting mixture was stirred for 16 h at 120° C. and then was diluted with 30 mL of water. The solution was extracted with 3×30 mL of ethyl acetate and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradiente of ethyl acetate/petroleum ether (1:30 to 1:20). This resulted in 3.2 g (80%) of the title compound as a yellow solid. MS-ESI: 203.1 (M+1).

Intermediate 42

8-(Difluoromethoxy)-1,2,3,5,6,7-hexahydro-s-indacen-4-amine Step 1: 1,2,3,5,6,7-Hexahydro-s-indacene

Into a 1-L round-bottom flask was placed a solution of 1,2,3,5,6,7-hexahydro-s-indacen-1-one (37.2 g, 216 mmol) and MSA (42 g, 437.5 mmol) in MeOH (300 mL). Then Pd(OH)₂/C (20% wt, 8 g) was added. The flask was evacuated and filled three times with hydrogen. The resulting solution was stirred for 16 h at RT under an atmosphere of hydrogen. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:150 to 1:100). This resulted in 27.1 g (79%) of the title compound as a white solid.

Step 2: 4-Bromo-1,2,3,5,6,7-hexahydro-s-indacene

Into a 500-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 1,2,3,5,6,7-hexahydro-s-indacene (15 g, 94.8 mmol) in CCl₄ (200 mL). Then I₂ (1.2 g, 4.72 mmol) was added. This was followed by the addition of a solution of Br₂ (16 g, 100 mmol) in CCl₄ (50 mL) dropwise with stirring at 0° C. in 10 min. The resulting solution was stirred for 2 h at 0° C. The reaction was then quenched by the addition of 150 mL of NH₄Cl (sat.). The resulting solution was extracted with 3×150 mL of DCM and the combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was purified by silica gel column with a gradient of ethyl acetate/hexane (1:500 to 1:100). This resulted in 19 g (85%) of the title compound as yellow oil. ¹H NMR (300 MHz, DMSO-d₆) δ 7.02 (s, 1H), 2.95-2.75 (m, 8H), 2.03-2.01 (m, 4H)

Step 3: 1,2,3,5,6,7-Hexahydro-s-indacen-4-ol

Into a 500-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 4-bromo-1,2,3,5,6,7-hexahydro-s-indacene (5 g, 21.08 mmol) in THF (150 mL). This was followed by the addition of n-BuLi (2.5 M in hexane, 10 mL) dropwise with stirring at −78° C. The resulting solution was stirred for 30 min at −78° C. Then to the above was added trimethyl borate (2.6 g, 25.30 mmol) dropwise with stirring at −78° C. The reaction was warmed to RT slowly and then was stirred for 1 h at RT. Then to the mixture was added AcOH (2.0 mL, 33.20 mmol) and H₂O₂ (1.0 mL, 28.88 mmol) dropwise with stirring at RT. The resulting solution was stirred for 2 h at RT and then was quenched by the addition of 200 mL of NH₄Cl (sat.). The resulting solution was extracted with 3×200 mL of DCM. The organic layers were combined and dried over anhydrous Na₂SO₄, then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:7 to 1:5). This resulted in 1.9 g (52%) of the title compound as an off-white solid. MS-ESI: 175.1 (M+1).

Step 4: 8-Nitro-1,2,3,5,6,7-hexahydro-s-indacen-4-ol

Into a 250-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-ol (1.9 g, 10.9 mmol) in EtOH (100 mL). To the solution was added 2,3,5,6-tetrabromo-4-methyl-4-nitrocyclohexa-2,5-dienone (6.1 g, 13.1 mmol). The resulting solution was stirred overnight at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in 1.1 g (46%) of the title compound as a light yellow solid. MS-ESI: 218.1 (M−1).

Step 5: 4-(Difluoromethoxy)-8-nitro-1,2,3,5,6,7-hexahydro-s-indacene

Into a 100-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-4-ol (1.1 g, 5.0 mmol) in DMF (20 mL) and water (2 mL). To the solution were added K₂CO₃ (1.4 g, 10.0 mmol) and sodium 2-chloro-2,2-difluoroacetate (1.5 g, 10.0 mmol). The resulting solution was stirred for 1 h at 120° C. and then was diluted with 20 mL of water. The pH value of the solution was adjusted to 7 with aq. HCl (1 N). The resulting solution was extracted with 3×20 mL of DCM. The organic layers were combined and dried over anhydrous Na₂SO₄, then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:2 to 1:3). This resulted in 0.55 g (41%) of the title compound as a light yellow solid. MS-ESI: 270.1 (M+1).

Step 6: 8-(Difluoromethoxy)-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

Into a 100-mL round-bottom flask was placed a solution of 4-(difluoromethoxy)-8-nitro-1,2,3,5,6,7-hexahydro-s-indacene (550 mg, 2.0 mmol) in MeOH (10 mL). Then Pd/C (10% wt., 100 mg) was added. The flask was evacuated and filled three times with hydrogen. The resulting solution was stirred for 12 h at RT under an atmosphere of hydrogen. The solids were filtered out. The resulting filtrate was concentrated under vacuum. This resulted in 460 mg (94%) of the title compound as a light yellow solid. MS-ESI: 240.1 (M+1).

3-Fluoro-2,6-diisopropylbenzenamine Step 1: 2,6-Dibromo-4-chloro-3-fluoroaniline

Into a 500-mL round-bottom flask was placed 4-chloro-3-fluoroaniline (5.08 g, 34.9 mmol), ACN (200 mL), and NBS (18.69 g, 105.0 mmol). The resulting solution was stirred for 12 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:200 to 1:100). This resulted in 9.7 g (92%) of the title compound as a light yellow solid. MS-ESI: 303.8/305.8/301.8 (M+1).

Step 2: 4-Chloro-3-fluoro-2,6-bis(prop-1-en-2-yl)aniline

Into a 500-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of 2,6-dibromo-4-chloro-3-fluoroaniline (9.03 g, 29.8 mmol) in 1,4-dioxane (200 mL) and water (20 mL). To the solution were added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (15.12 g, 89.98 mmol), Cs₂CO₃ (29.34 g, 90.1 mmol) and Pd(dppf)Cl₂ (2.20 g, 3.0 mmol). The resulting solution was stirred for 12 h at 90° C. and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:30 to 1:20). This resulted in 4.3 g (64%) of the title compound as yellow oil. MS-ESI: 226.1, 228.1 (M+1).

Step 3: 3-Fluoro-2,6-bis(propan-2-yl)aniline

Into a 100-mL round-bottom flask was placed a solution of 4-chloro-3-fluoro-2,6-bis(prop-1-en-2-yl)aniline (1 g, 4.4 mmol) in MeOH (15 mL). Then Pd/C(10% wt., 100 mg) was added. The flask was evacuated and filled three times with hydrogen. The resulting solution was stirred for 3 h at RT under an atmosphere of hydrogen. The solids were filtered out. The resulting filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in 700 mg (81%) of the title compound as light yellow oil. MS-ESI: 196.1 (M+1).

Intermediate 44

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene Step 1: 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene

Into a 50-mL round-bottom flask purged with and maintained under nitrogen was placed 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (64 mg, 0.4 mmol), THF (5 mL) and BTC (37 mg, 0.1 mmol). The resulting solution was stirred for 2 h at 65° C. and then was concentrated under vacuum. This resulted in 75 mg (crude) of the title compound as light brown oil. The crude product was used directly in the next step.

TABLE 9 The Intermediates in the following Table was prepared using similar procedure as shown in Scheme 30 above for converting compound 130” to Intermediate 44. Intermediate # Structure IUPAC Name Intermediate 45

5-Fluoro-2-isocyanato-1,3- diisopropylbenzene Intermediate 46

2-Fluoro-4-isocyanato-3,5- diisopropylbenzonitrile Intermediate 47

5-(Difluoromethoxy)-2-isocyanato- 1,3-diisopropylbenzene Intermediate 48

5-(Difluoromethoxy)-1-ethyl-2-isocyanato-3- isopropylbenzene Intermediate 49

1-Cyclopropyl-5-(difluoromethoxy)-2-isocyanato-3- isopropylbenzene Intermediate 50

4-Chloro-8-isocyanato-1,2,3,5,6,7- hexahydro-s-indacene Intermediate 51

4-Fluoro-8-isocyanato-1,2,3,5,6,7- hexahydro-s-indacene Intermediate 52

5-Cyclopropyl-2-fluoro-4-isocyanato-3- isopropylbenzonitrile Intermediate 53

4-Isocyanato-3,5-diisopropylbenzonitrile Intermediate 54

1,2,3,5,6,7-Hexahydro-8-isocyanato-s- indacene-4-carbonitrile Intermediate 55

4-(Difluoromethoxy)-1,2,3,5,6,7- hexahydro-8-isocyanato-s- indacene Intermediate 56

1-Fluoro-3-isocyanato-2,4-diisopropylbenzene Intermediate 57

1,2,3,5,6,7-Hexahydro-8-isocyanato- 1-methyl-s-indacene Intermediate 58

1,2,3,5,6,7-Hexahydro-4-isocyanato- 1-methyl-s-indacene

The following schemes illustrate additional general methods for the synthesis of compounds of Formula AA:

Scheme for the preparation of Sulfonimidamide Intermediates: Schemes below illustrate the preparation of sulfonimidamide intermediates 59-88 and 112-113.

Intermediate 59

N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonimidamide Step 1: Ethyl 3-nitro-1-phenyl-1H-pyrazole-5-carboxylate

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 3-nitro-1H-pyrazole-5-carboxylate (5.0 g, 27.0 mmol), THF (150 mL), phenylboronic acid (6.6 g, 54.1 mmol), Cu(OAc)₂ (7.38 g, 40.6 mmol), and pyridine (8.54 g, 108 mmol). The resulting solution was stirred overnight at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 3.1 g (44%) of the title compound as an off-white solid. MS-ESI: 262 (M+1).

Step 2: Ethyl 3-amino-1-phenyl-1H-pyrazole-5-carboxylate

Into a 100-mL round-bottom flask, was placed ethyl 3-nitro-1-phenyl-1H-pyrazole-5-carboxylate (3.92 g, 15.0 mmol), MeOH (50 mL), and Pd/C (wet 10% wt., 400 mg). The flask was evacuated and filled three times with hydrogen. The resulting solution was stirred overnight at RT. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 2.8 g (81%) of the title compound as a light yellow solid. MS-ESI: 232 (M+1).

Step 3: Ethyl 3-(chlorosulfonyl)-1-phenyl-1H-pyrazole-5-carboxylate

Into a 100-mL round-bottom flask, was placed ethyl 3-amino-1-phenyl-1H-pyrazole-5-carboxylate (1.8 g, 7.78 mmol), HCl (cc. 6.0 mol/L, 15 mL). This was followed by the addition of a solution of NaNO₂ (646 mg, 9.36 mmol) in water (2.0 mL) dropwise with stirring at −10° C. The resulting solution was stirred for 30 min at −10° C. The above mixture was added to a saturated solution of SO₂ in AcOH (20 mL) dropwise with stirring at 0° C. Then to the above was added CuCl₂ (1.05 g, 7.81 mmol). The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 3×30 mL of DCM and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 2.2 g (90%) of the title compound as a light yellow solid.

Step 4: Ethyl 1-phenyl-3-sulfamoyl-1H-pyrazole-5-carboxylate

Into a 100-mL round-bottom flask, was placed a solution of ethyl 3-(chlorosulfonyl)-1-phenyl-1H-pyrazole-5-carboxylate (2.2 g, 6.99 mmol) in DCM (10 mL). Then to the above was introduced NH₃ gas bubbled at 0° C. for 10 min. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 1.07 g (52%) of the title compound as a light yellow solid. MS-ESI: 296 (M+1).

Step 5: 5-(2-Hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonamide

Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl 1-phenyl-3-sulfamoyl-1H-pyrazole-5-carboxylate (1.65 g, 5.59 mmol) in THF (30 mL). This was followed by the addition of MeMgBr/THF (3.0 M, 18.6 mL) dropwise with stirring at 0° C. The resulting solution was stirred overnight at RT. The reaction was then quenched by the addition of 30 mL of NH₄Cl (sat.). The resulting solution was extracted with 3×30 mL of DCM and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (2:1). This resulted in 1.35 g (86%) of the title compound as a yellow solid. MS-ESI: 282 (M+1).

Step 6: N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonamide

Into a 100-mL round-bottom flask, was placed 5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonamide (500 mg, 1.78 mmol), THF (10 mL). This was followed by the addition of sodium hydride (60% wt. oil dispersion, 86 mg, 3.58 mmol) in portions at 0° C. Then to the above was added TBSCl (538 mg, 3.57 mmol). The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 660 mg (94%) of the title compound as a light yellow solid. MS-ESI: 396 (M+1).

Step 7: N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonimidamide

Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed the solution of PPh₃Cl₂ (1.67 g, 5.01 mmol) in chloroform (30 mL). This was followed by the addition of DIEA (1.29 g, 9.98 mmol) dropwise with stirring at RT. The resulting solution was stirred for 10 min at RT and the reaction system was cooled to 0° C. To this was added a solution of N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonamide (660 mg, 1.67 mmol) in chloroform (3.0 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 30 min at 0° C. To the mixture was added introduced NH₃ gas bubble for 15 min at 0° C. The resulting solution was stirred for 2 h at RT. The resulting solution was diluted with 30 mL of water. The resulting solution was extracted with 3×30 mL of DCM and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 530 mg (81%) of the title compound as a light yellow solid. MS-ESI: 395 (M+1).

Intermediate 60

N′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylthiazole-2-sulfonimidamide

Steps 1-6 used similar procedures for converting compound 16 to intermediate 2 shown in Scheme 7B to afford intermediate 60 from compound 151″. MS-ESI: 350 (M+1).

Intermediate 61

N-methyl-N-(4-sulfamoylbenzyl)acetamide Intermediate 62

N-(4-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)benzyl)-N-methylacetamide Step 1: N-benzyl-N-methylacetamide

Into a 1.0 L round-bottom flask were added benzyl(methyl)amine (10 g, 82.5 mmol) and DCM (500 mL) at 0° C. . To this stirred solution were added DIEA (21.3 g, 165 mmol) and acetyl chloride (9.72 g, 124 mmol) in portions at 0° C. The resulting mixture was stirred for 4 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1) to afford the title compound (13 g, 96.5%) as a yellow oil. MS-ESI: 164 (M+1).

Step 2: 4-((N-methylacetamido)methyl)benzenesulfonyl chloride

Into a 250 mL round-bottom flask were added N-benzyl-N-methylacetamide (3.0 g, 18.4 mmol,) and DCM (6.0 mL) at 0° C. To this stirred solution were added ClSO₂OH (6.0 mL) in one portion at 0° C. The resulting mixture was stirred for 3 h at RT. The reaction was quenched by the addition of water/ice (150 mL) at 0° C. The resulting solution was extracted with 3×150 mL of DCM and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product of the title compound (2.2 g, 45.7%)) was used in the next step directly without further purification.

Step 3: N-methyl-N-(4-sulfamoylbenzyl)acetamide

Into a 250 mL round-bottom flask were added 4-[(N-methylacetamido)methyl]benzene-1-sulfonyl chloride (2.2 g, 8.41 mmol) and DCM (3.0 mL) at 0° C. . To this stirred solution were added NH₃(g) in DCM (40 mL) dropwise at 0° C. The resulting mixture was stirred overnight at RT. The resulting mixture was concentrated under reduced pressure. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1) to afford the minor compound 159B (122 mg, 6.1%) and the title compound (1.9 g, 93.3%) both as white solids. MS-ESI: 243 (M+1).

Step 4-6 used similar procedures for converting compound 148″ to intermediate 59 shown in Scheme 36 to afford intermediate 62 from intermediate 61. MS-ESI: 356 (M+1).

TABLE 10 Intermediate 62B in the following Table was prepared using similar procedures for converting compound 157” to Intermediate 62 shown in Scheme 38 from compound 159”B which was separated from step 3 in Scheme 38. The Intermediate 63 was prepared using similar procedures for converting compound 157” to Intermediate 62 shown in Scheme 38 from appropriate starting materials. Exact Intermediate Mass # Structure IUPAC Name [M + H]⁺ Intermediate 62B

N-(3-(N′-(tert-butyldimethylsilyl) sulfamimidoyl)benzyl)-N- methylacetamide 356 Intermediate 63

N′-(tert-butyldimethylsilyl)-2-fluoro-4- methoxybenzenesulfonimidamide 319

Intermediate 64

4-((Methylamino)methyl)benzenesulfonamide Intermediate 65

N-(4-(N′-(tert-butyldimethylsilyl)sulfamimidoyl)benzyl)-N-methylpent-4-ynamide Step 1: 4-((Methylamino)methyl)benzenesulfonamide

Into a 500-mL sealed tube, was placed N-methyl-N-[(4-sulfamoylphenyl)methyl]acetamide (5.0 g), hydrogen chloride (200 mL, 12 M). The resulting solution was stirred for 16 h at 100° C. in an oil bath. The resulting mixture was concentrated. This resulted in 5.0 g of the title compound as an off-white crude solid. MS-ESI: 201 (M+1)

Step 2: N-methyl-N-(4-sulfamoylbenzyl)pent-4-ynamide

Into a 250 mL round-bottom flask was placed 4-((methylamino)methyl)benzenesulfonamide (4.0 g, 20 mmol) in DMF (40 mL). To this stirred solution was added HATU (6.33 g,16.7 mmol), DIEA (5.16 g, 40 mmol) and pent-4-ynoic acid (2.16 g, 22 mmol). Then the mixture was stirred overnight RT. The resulting solution was diluted with 40 mL of water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 2.97 g (53%) of the title compound as a light yellow solid. MS-ESI: 281 (M+1).

Steps 3-5 used similar procedures for converting Intermediate 61 to Intermediate 62 shown in Scheme 38 to afford Intermediate 65 from compound 163″. MS-ESI: 394 (M+1).

Intermediate 66

Tert-butyl 4-(N′-(tert-butyldimethylsilyl)sulfamimidoyl)benzyl(methyl)carbamate Intermediate 67

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-((methylamino)methyl)benzenesulfonimidamide Step 1: Tert-butyl methyl(4-sulfamoylbenzyl)carbamate

Into a 250-mL round-bottom flask, was placed 4-[(methylamino)methyl]benzene-1-sulfonamide (5.0 g, 25 mmol) in DCM (100 mL). To this stirred solution was added di-tert-butyl dicarbonate (6.0 g, 27.5 mmol). The resulting solution was stirred for 5 h at RT. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 5.0 g (66.7%) of the title compound as a light yellow solid. MS-ESI: 301 (M+1).

Steps 2-4 used similar procedures for converting compound 148″ to intermediate 59 shown in Scheme 36 to afford Intermediate 66 from compound 166″. MS-ESI: 414 (M+1).

Step 5: Tert-butyl(4-(N-(tert-butyldimethylsilyl)-N′4(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-sulfamidimidoyl)benzyl)(methyl)carbamate

Into a 50-mL round-bottom flask, was placed tert-butyl (4-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)benzyl)(methyl)carbamate (500 mg, 1.21 mmol) in THF (15 mL). To this stirred solution was added 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (343 mg, 1.81 mmol) and NaH (60% wt. oil dispersion, 96.8 mg, 2.42 mmol). The resulting solution was stirred for 3 h at RT. The reaction was quenched by the addition of MeOH (10 mL). This resulted in 500 mg (67.5%) of the title compound as a white crude solid. MS-ESI: 613 (M+1).

Step 6: N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-((methylamino)methyl)benzenesulfonimidamide

Into a 50-mL round-bottom flask was placed tert-butyl N-[(4-[[(tert-butyldimethylsilyl)amino] ([[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]imino])oxo-λ⁶-sulfanyl]phenyl)methyl]-N-methylcarbamate (90 mg) and HCl in dioxane (4 M, 5.0 mL). The resulting solution was stirred for 16 h at RT. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC with the following conditions: Column, Sunfire Prep C18 OBD,10 um,19*250 mm; mobile phase A: water (0.05% TFA) and B: ACN (20% to 50% gradient of B over 17 min); Detector, UV 220/254 nm. This resulted in 30 mg of the title compound as a white solid. MS-ESI: 399 (M+1).

Intermediate 70

N′-(tert-butyldimethylsilyl)-6-(2-hydroxypropan-2-yl)-2-methylpyridine-3-sulfonimidamide Step 1: Methyl 5-amino-6-methylpicolinate

Into a 50-mL seal tube was placed methyl 6-bromo-2-methylpyridin-3-amine (500 mg, 2.67 mmol) in MeOH (15 mL) and Pd(OAc)₂ (120 mg, 0.53 mmol), dppf (444 mg, 0.80 mmol), TEA (809 mg, 8.01 mmol). The seal tube was evacuated and flushed three times with CO. The resulting solution was stirred for 5 h at 100° C. under 10 atm of CO. Then the solution was concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 351 mg (79.2%) of the title compound as a light yellow solid. MS-ESI: 167 (M+1).

Steps 2-4 used similar procedures for converting compound 27 to Intermediate 30 shown in Scheme 9 to afford compound 176″ from compound 173″. MS-ESI: 231 (M+1).

Steps 5-6 used similar procedures for converting compound 148″ to intermediate 59 shown in Scheme 36 to afford Intermediate 70 from compound 176″. MS-ESI: 344 (M+1).

TABLE 11 The Intermediates in the following Table were prepared using the similar procedures for converting compound 172″ to Intermediate 70 shown in Scheme 42 from appropriate starting materials. Intermediate Exact Mass # Structure IUPAC Name [M + H]⁺ Intermediate 71

N′-(tert-butyldimethylsilyl)- 6-(2-hydroxypropan-2- yl)pyridine-3-sulfonimidamide 330

Intermediate 72

N′-(tert-butyldimethylsilyl)-4-(2-methoxypropan-2-yl)benzenesulfonimidamide Step 1: 1-Bromo-4-(2-methoxypropan-2-yl)benzene

Into a 250-mL round-bottom flask, was placed a solution of 2-(4-bromophenyl)propan-2-ol (10 g, 46.5 mmol) in THF (50 mL). To this stirred solution was added NaH (60% wt. oil dispersion, 5.19 g, 93 mmol) at 0° C. The resulting solution was stirred for 30 min at 0° C. To this stirred solution was added MeI (6.60 g, 46.5 mmol) dropwise with stirring at 0° C. The resulting solution was allowed to react for an additional 15 h at RT. The resulting solution was quenched with 40 mL of water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (15/85). This resulted in 8.5 g (50.3%) of the title compound as a yellow solid.

Step 2: 4-(2-Methoxypropan-2-yl)benzenesulfinic acid

Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1-bromo-4-(2-methoxypropan-2-yl)benzene (5.0 g, 21.8 mmol) in THF (50 mL). To this stirred solution was added n-BuLi (13 mL, 32.7 mmol, 2.5 M) dropwise with stirring at −78° C. The resulting solution was stirred for 30 min at −78° C. SO₂(g) was introduced into the stirring solution at −78° C. The resulting solution was allowed to react for an additional 60 min at RT. The resulting mixture was concentrated. This resulted in 6.0 g (crude) of the title compound as a yellow solid. MS-ESI: 213 (M−1)

Step 3: 4-(2-Methoxypropan-2-yl)benzenesulfonyl chloride

Into a 50-mL round-bottom flask, was placed 4-(2-methoxypropan-2-yl)benzene-1-sulfinic acid (4.9 g, 22.9 mmol) in THF (50 mL). To this stirred solution was added NCS (4.58 g, 34.3 mmol). The resulting solution was stirred for 30 min at 0° C. The mixture was allowed to react for an additional 60 min at RT. NH₃ (g) was introduced into the reaction solution. The resulting solution was allowed to react for an additional 120 min at RT. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1/4). This resulted in 4.3 g (82%) of the title compound as a yellow solid.

Step 4: 4-(2-Methoxypropan-2-yl)benzenesulfonamide

Into a 250-mL round-bottom flask was placed 4-(2-methoxypropan-2-yl)benzene-1-sulfonyl chloride (4.3 g, 17.3 mmol) in DCM (50 mL). NH₃ (g) was introduced into the reaction solution at 0° C. The resulting solution was stirred for 180 min at RT. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1/3). This resulted in 3.9 g (98.5%) of the title compound as a yellow solid. MS-ESI: 230 (M+1).

Step 5: N-(tert-butyldimethylsilyl)-4-(2-methoxypropan-2-yl)benzenesulfonamide

Into a 100-mL round-bottom flask, was placed a solution of 4-(2-methoxypropan-2-yl)benzene-1-sulfonamide (4.0 g, 17.5 mmol) in THF (40 mL). To this stirred solution was added NaH (1.4 g, 34.9 mmol, 60% wt. oil dispersion) and TBSCl (3.16 g, 21 mmol) at 0 C. The resulting solution was allowed to react with stirring for 15 h at RT. The resulting solution was quenched with 40 mL of water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (30/70). This resulted in 2.3 g (38.4%) of the title compound as a yellow solid. MS-ESI: 344 (M+1)

Step 6: N′-(tert-butyldimethylsilyl)-4-(2-methoxypropan-2-yl)benzenesulfonimidamide

Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed the solution of PPh₃Cl₂ (12.4 g, 37.3 mmol) in chloroform (150 mL). This was followed by the addition of DIEA (9.63 g, 74.5 mmol) dropwise with stirring at RT. The resulting solution was stirred for 10 min at RT and the reaction system was cooled to 0° C. To this was added a solution of N-(tert-butyldimethylsilyl)-4-(2-methoxypropan-2-yl)benzene-1-sulfonamide (3.2 g, 9.31 mmol) in chloroform (30 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 30 min at 0° C. To the mixture was introduced NH₃ gas bubble for 15 min at 0° C. The resulting solution was stirred for 2 h at RT. The resulting solution was diluted with 100 mL of water. The resulting solution was extracted with 3×200 mL of DCM and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (36/64). This resulted in 1.4 g (36.5%) of the title compound as a yellow solid. MS-ESI: 343 (M+1)

Intermediate 73

N′-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)pyridine-2-sulfonimidamide Step 1: (6-Bromopyridin-3-yl)-N,N-dimethylmethanamine

Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed Ti(OEt)₄ (12.3 g, 53.8 mmol) and dimethylamine (4.85 g, 108 mmol) in MeOH (50 mL) at RT. To a stirred solution was added 6-bromopyridine-3-carbaldehyde (5.0 g, 26. 9 mmol) in MeOH (30 mL) dropwise at 0° C. Then the reaction solution was stirred at RT for 3 h. NaBH₄ (1.02 g, 26.9 mmol) was added to the mixture and the resulting solution was stirred over night at RT. The reaction was quenched by the addition of water/ice (30 mL) at 0° C. The resulting mixture was concentrated under reduced pressure. Then the resulting mixture extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (5:1) to afford the title compound (3.5 g, 60.5%) as a yellow oil. MS-ESI: 216/218 (M+1).

Steps 2-6 used similar procedures for converting compound 179″ to Intermediate 72 shown in Scheme 43 to afford Intermediate 73 from compound 185. MS-ESI: 329 (M+1).

TABLE 12 The Intermediates in the following Table were prepared using the similar procedures for converting compound 184″ to Intermediate 73 shown in Scheme 44 from appropriate starting materials. Exact Intermediate Mass # Structure IUPAC Name [M + H]⁺ Intermediate 74

N′-(tert-butyldimethylsilyl)-6- ((dimethylamino)methyl) pyridine-3-sulfonimidamide 329

Intermediate 75

N′-(tert-butyldimethylsilyl)-1-methyl-1H-indazole-5-sulfonimidamide

Steps 1-6 used similar procedures for converting compound 179″ to Intermediate 72 shown in Scheme 43 to afford Intermediate 75 from compound 190″. MS-ESI: 325 (M+1).

Intermediate 76

N′-(tert-butyldimethylsilyl)-4-(2-(dimethylamino)propan-2-yl)benzenesulfonimidamide Step 1: 4-(Prop-1-en-2-yl)benzenesulfonamide

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-bromobenzene-1-sulfonamide (5.0 g, 21.2 mmol) in dioxane (100 mL) and H₂O (15 mL). To this stirred solution was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (14.2 g, 84.7 mmol), Pd(dppf)Cl₂ (4.65 g, 6.35 mmol) and Cs₂CO₃ (13.8 g, 42.4 mmol). The resulting solution was stirred for 15 h at 100° C. The resulting mixture was concentrated under reduced pressure. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (40/60). This resulted in 3.6 g (86.2%) of the title compound as a yellow solid. MS-ESI: 198 (M+1).

Step 2: 2-Chloro-N-(2-(4-sulfamoylphenyl)propan-2-yl)acetamide

Into a 1.0-L round-bottom flask, was placed 4-(prop-1-en-2-yl)benzene-1-sulfonamide (5.0 g, 25.4 mmol) in H₂SO₄ (50 mL) and AcOH (250 mL). To the stirred solution was added 2-chloroacetonitrile (38.3 g, 507 mmol). The resulting solution was stirred for 30 min at 0° C. The resulting solution was allowed to react for an additional 15 h at RT. The pH value of the solution was adjusted to 7 with Na₂CO₃ (5.0 M). Then the resulting mixture was extracted with ethyl acetate (3×200 mL) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (2/3). This resulted in 4.2 g (57%) of the title compound as yellow oil. MS-ESI: 291 (M+1).

Step 3: 4-(2-Aminopropan-2-yl)benzenesulfonamide

Into a 250-mL round-bottom flask, was placed 2-chloro-N-[2-(4-sulfamoylphenyl)propan-2-yl]acetamide (4.2 g, 14.5 mmol) in CH₃COOH (15 mL) and ethanol (75 mL). To this stirred solution was added thiourea (1.32 g, 17.3 mmol). The resulting solution was stirred for 16 h at 85° C. The resulting mixture was washed with 100 ml of H₂O and extracted with 3×250 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 2.3 g (54.3%) of the title compound as a yellow solid. MS-ESI: 215 (M+1).

Step 4: 4-(2-(Dimethylamino)propan-2-yl)benzenesulfonamide

Into a 250-mL round-bottom flask, was placed 4-(2-aminopropan-2-yl)benzene-1-sulfonamide (2.14 g, 9.99 mmol) in MeOH (50 mL). To this stirred solution was added HCHO (37% wt., 599 mg, 20 mmol) and NaBH₃CN (1.86 g, 30 mmol). The resulting solution was stirred for 120 min at RT. The resulting mixture was diluted with 100 mL of water and extracted with 3×250 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (30/70). This resulted in 1.0 g (41.3%) of the title compound as a yellow solid. MS-ESI: 243 (M+1).

Steps 5-7 used similar procedures for converting compound 148″ to intermediate 59 shown in Scheme 36 to afford Intermediate 76 from compound 200. MS-ESI: 356 (M+1).

Intermediate 77

N′-(tert-butyldimethylsilyl)-4-(1-(dimethylamino)ethyl)benzenesulfonimidamide Step 1: (E)-4-(1-((tert-butylsulfinyl)imino)ethyl)benzenesulfonamide

Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added 2-methylpropane-2-sulfinamide (3.04g, 25.1 mmol) in THF (50 mL). To this stirred solution was added Ti(OEt)₄(11.5 g, 50.2 mmol) and 4-acetylbenzene-1-sulfonamide (5.0 g, 25.1 mmol) in portions at RT. The resulting mixture was stirred for overnight at 70° C. under nitrogen atmosphere. The reaction was quenched with Water (20 mL) at 0° C. The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate/petroleum ether (1:1) to afford the title compound (5.0 g,75.8%) as a yellow solid. MS-ESI: 303 (M+1).

Step 2: 4-(1-((Tert-butylsulfinyl)amino)ethyl)benzenesulfonamide

Into a 500 mL round-bottom flask were added 4-[(1E)-1-[(2-methylpropane-2-sulfinyl)imino]ethyl]benzene-1-sulfonamide (4.65 g, 15.4 mmol) in THF (200 mL) at RT. To this stirred solution was added NaBH₄ (1.16 g, 30.8 mmol) in portions at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 4 h at RT under nitrogen atmosphere. The reaction was quenched by the addition of HCl (2M, 50 mL) at 0° C. The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (4.5 g, 96.1%) as a white solid. MS-ESI: 305 (M+1).

Step 3: 4-(1-Aminoethyl)benzenesulfonamide

Into a 250 mL round-bottom flask were added 4-[1-[(2-methylpropane-2-sulfinyl)amino]ethyl]benzene-1-sulfonamide (4.4 g, 14.5 mmol) and MeOH (50 mL) at room temperature. To this stirred solution was added HCl (gas) in 1,4-dioxane (8.0 mL, 26.3 mmol) in one portions at RT. The resulting mixture was stirred overnight at RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm.) to afford the title compound (2.6 g, 89.7%) as a white solid. MS-ESI: 201 (M+1).

Step 4: 4-(1-(Dimethylamino)ethyl)benzenesulfonamide

Into a 250 mL round-bottom flask was added 4-(1-aminoethyl)benzene-1-sulfonamide (2.0 g, 9.99 mmol) and MeOH (60 mL) at RT. To this stirred solution was added HCHO (37% wt., 1.61 g, 53.6 mmol) and NaBH₃CN (1.25 g, 20 mmol) in portions at RT. The resulting mixture was stirred overnight at RT. The reaction solution was diluted with 100 mL of water and extracted with 3×100 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether. The residue was purified by silica gel column chromatography, eluted with ethyl acetate/petroleum ether (1:2) to afford the title compound (1.5 g, 65.8%) as a white solid. MS-ESI: 229 (M+1).

Steps 5-7 used similar procedures for converting compound 148″ to intermediate 59 shown in Scheme 36 to afford Intermediate 77 from compound 207″. MS-ESI: 342 (M+1).

Intermediate 78

4-(2-Hydroxypropan-2-yl)-N,N-dimethylthiophene-2-sulfonimidamide Step 1: N′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-N,N-dimethylthiophene-2-sulfonimidamide

Into a 50-mL 3-necked round-bottom flask, was placed N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl) thiophene-2-sulfonoimidamide (300 mg, 0.90 mmol) in THF (3.0 mL). To the solution were added NaH (60% wt. oil dispersion, 53.8 mg, 1.35 mmol) at −10° C. in ethanol/ice bath. To the solution were added iodomethane (0.50 mL) dropwise with stirring at 0° C. in 30 min. The resulting solution was stirred for 30 min at RT. The reaction was then quenched by the addition of NH₄Cl (aq.). The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 252 mg (77.5%) of the title compound as a white solid. MS-ESI: 363 (M+1).

Step 2: N′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-N,N-dimethylthiophene-2-sulfonimidamide

Into a 50-mL round-bottom flask, was placed N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-N,N-dimethylthiophene-2-sulfonoimidamide (200 mg, 0.55 mmol) in THF (10 mL). To the solution was added HF/Py (70% wt., 0.10 mL) dropwise with stirring at RT. The resulting solution was stirred for 60 min at RT. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with ethyl acetate (3×10 mL), the organic layers combined and dried over anhydrous sodium sulfate. The residue was eluted from a silica gel column with ethyl acetate. This resulted in 127 mg (92.7%) of the title compound as a white solid. MS-ESI: 249 (M+1).

Intermediate 79

2-(2-Hydroxypropan-2-yl)-N-methylthiazole-5-sulfonimidamide Step 1: Tert-butyl (chloro(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ⁶-sulfaneylidene)carbamate

Into a 1.0-L round-bottom flask, was placed tert-butyl N-[[2-(2-hydroxypropan-2-yl)-1,3-thiazol-5-yl] sulfinyl]carbamate (100 g, 326 mmol) in ACN (500 mL). To the stirred solution was added NCS (65.4 g, 490 mmol). The resulting solution was stirred for 2 h at RT. The resulted solution was concentrated. This resulted in 120 g (crude) of the title compound as yellow oil. MS-ESI: 341/343 (M+1).

Step 2: Tert-butyl((2-(2-hydroxypropan-2-yl)thiazol-5-yl)(methylamino)(oxo)-λ⁶-sulfaneylidene) carbamate

Into a 250-mL round-bottom flask, was placed tert-butyl (chloro(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ⁶-sulfaneylidene)carbamate (10 g, 29.3 mmol) in THF (100 mL). To the stirred solution was added CH₃NH₂ (1.82 g, 58.6 mmol). The resulting solution was stirred for 2 h at RT. The resulted solution was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 6.1 g (62%) of the title compound as a yellow solid. MS-ESI: 336 (M+1).

Step 3: 2-(2-Hydroxypropan-2-yl)-N′-methylthiazole-5-sulfonimidamide

Into a 100-mL round-bottom flask, was placed tert-butyl((2-(2-hydroxypropan-2-yl)thiazol-5-yl)(methylamino)(oxo)-λ⁶-sulfaneylidene) carbamate (3.0 g, 8.94 mmol) in HCl (gas) in 1,4-dioxane (8 mL, 26.3 mmol) in one portion at RT. The resulting solution was stirred for 60 min at RT. The resulting mixture was concentrated under vacuum. This resulted in 2.10 g (crude) of the title compound as a yellow solid. MS-ESI: 236 (M+1).

Intermediate 80

Tert-butyl (amino(2-(2-methoxypropan-2-yl)thiazol-5-yl)(oxo)-λ⁶-sulfaneylidene)carbamate Step 1: Methyl 2-(2-methoxypropan-2-yl)thiazole-5-sulfinate

Into a 1-L round-bottom flask, was placed a solution of methyl 2-(2-hydroxypropan-2-yl)-1,3-thiazole-5-sulfinate (40 g, 181 mmol) in THF (500 mL). To this stirred solution was added NaH (60% wt oil dispersion, 7.95 g, 199 mmol) in three portions at 0° C. in an ice/ethanol bath. To this reaction solution was added MeI (51.3 g, 362 mmol) dropwise with stirring at 0° C. in an ice/ethanol bath. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of water (50 mL) at 0° C. The resulting solution was extracted with 3×300 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 32 g (75.3%) of the title compound as a white solid. MS-ESI: 236 (M+1).

Step 2: 2-(2-Methoxypropan-2-yl)thiazole-5-sulfinamide

Into a 1-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 2-(2-methoxypropan-2-yl)-1,3-thiazole-5-sulfinate (20 g, 85 mmol) in THF (500 mL). This was followed by the addition of KHMDS (500 mL, 1.0 mole, 2 M) dropwise with stirring at −78° C. in a liquid nitrogen/ethanol bath. The resulting solution was stirred for 3 h at −78° C. in a liquid nitrogen/ethanol bath. The reaction was quenched by the addition of water (50 mL). The resulting solution was extracted with 3×300 mL of ethyl acetate dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 14 g (74.8%) of the title compound as a white solid. MS-ESI: 221.0 (M+1).

Step 3: Tert-butyl ((2-(2-methoxypropan-2-yl)thiazol-5-yl)sulfinyl)carbamate

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-(2-methoxypropan-2-yl)-1,3-thiazole-5-sulfinamide (10 g, 45.4 mmol) in THF (250 mL). To this stirred solution was added NaH (60% wt. oil dispersion, 3.63 g, 90.8 mmol) in three times at 0° C. in an ice/ethanol bath. To this solution was added Boc₂O (9.91 g, 45.4 mmol) in portions at 0° C. in an ice/ethanol bath. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of water (50 mL). The resulting solution was extracted with 3×300 mL of ethyl acetate concentrated under vacuum. This resulted in 12 g (82.5%) of the title compound as a white solid. MS-ESI: 321.1 (M+1).

Step 4: Tert-butyl (chloro(2-(2-methoxypropan-2-yl)thiazol-5-yl)(oxo)-λ⁶-sulfaneylidene)carbamate

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl N-[[2-(2-methoxypropan-2-yl)-1,3-thiazol-5-yl]sulfinyl]carbamate (11 g, 34.3 mmol) in THF (200 mL). NCS (13.8 g, 103 mmol) was added to the reaction solution in one portion at RT. The resulting solution was stirred for 3 h at RT. This reaction solution was used to the next step directly without further purification.

Step 5: Tert-butyl (amino(2-(2-methoxypropan-2-yl)thiazol-5-yl)(oxo)-λ⁶-sulfaneylidene)carbamate

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl N-[[2-(2-methoxypropan-2-yl)-1,3-thiazol-5-yl]sulfinyl]carbamate (9.0 g, 28.9 mmol) in THF (200 mL). To the mixture was added introduced NH₃ gas bubble for 15 min at 0° C. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 7g (72.3%) of the title compound as a white solid. MS-ESI: 336.1 (M+1).

Intermediate 81

N′-(tert-butyldimethylsilyl)-6-isobutylpyridine-3-sulfonimidamide

Steps 1-2 used similar procedures for converting compound 27 to Intermediate 29 shown in Scheme 9 to afford compound 219″ from compound 217″. MS-ESI: 238 (M+1).

Step 3: 6-(2-Methylprop-1-enyl)pyridine-3-sulfonamide

Into a 500 mL round-bottom flash were added 6-bromopyridine-3-sulfonamide (5.5 g, 23.2 mmol) and dioxane (150 mL) and water (15 mL) at RT. To this solution was added Pd(dppf)Cl₂ (1.7 g, 2.32 mmol), Cs₂CO₃ (15.1 g, 46.4 mmol) and 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane (8.45 g, 46.4 mmol) in one portion at RT under nitrogen atmosphere. The resulting mixture was stirred overnight at 100° C. under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:1) to afford title compound (4.0 g, 81.2%) as a light yellow oil. MS-ESI: 213 (M+1).

Step 4: 6-Isobutylpyridine-3-sulfonamide

Into a 250 mL 3-necked round-bottom flask was added 6-(2-methylprop-1-en-1-yl)pyridine-3-sulfonamide (4 g, 18.8 mmol) and MeOH (100 mL) at RT under nitrogen atmosphere. To this stirred solution was added Pd/C (wet 10% wt., 900 mg). The flask was evacuated and filled three times with hydrogen. The resulting mixture was stirred overnight at RT under hydrogen atmosphere. The resulting mixture was filtered; the filter cake was washed with MeOH (3×20 mL). The filtrate was concentrated under reduced pressure. The crude product of the title compound (3.8 g) was used to the next step directly without further purification. MS-ESI: 215 (M+1).

Steps 5-7 used similar procedures for converting compound 148″ to intermediate 59 shown in Scheme 36 to afford intermediate 81 from compound 221″. MS-ESI: 328 (M+1).

TABLE 13 The Intermediates in the following Table were prepared using the similar procedures for converting compound 217″ to Intermediate 81 shown in Scheme 51 from appropriate starting materials. Intermediate Exact Mass # Structure IUPAC Name [M + H]⁺ Intermediate 82

N′-(tert-butyldimethylsilyl)-4- isobutylbenzenesulfonimidamide 327

Intermediate 83

N-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)methyl)benzenesulfonimidamide Example 233 (Compound 342)

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(hydroxymethyl)benzenesulfonimidamide Step 1: 4-(Hydroxymethyl)benzenesulfonamide

Into a 100-mL round-bottom flask, was placed 4-sulfamoylbenzoic acid (1.0 g, 4.97 mmol) in THF (15 mL). This was followed by the addition of BH₃-THF (14.3 mL, 149 mmol) dropwise with stirring at 0° C. in an ice/ethanol bath. The resulting solution was stirred for 12 h at RT. The reaction was then quenched by the addition of HCl (50 mL, 2 M) dropwise in an ice bath and stirred for 1 h at RT. The mixture was extracted with 8×50 mL of ethyl acetate. The organic layers were combined and concentrated. This resulted in 800 mg (86%) of the title compound as a yellow solid. MS-ESI: 188 (M+1).

Steps 2-3 used similar procedures for converting compound 148″ to Intermediate 59 shown in Scheme 36 to afford Intermediate 83 from compound 225″. MS-ESI: 415 (M+1).Steps 4-5 used similar procedures for converting compound 166″ to Intermediate 67 shown in Scheme 40A to afford compound Example 233 from Intermediate 83. MS-ESI: 386 (M+1).

Intermediate 84

4-(Bromomethyl)-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)benzenesulfonimidamide Step 6: 4-(Bromomethyl)-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)benzenesulfonimidamide

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1-[amino[4-(hydroxymethyl)phenyl]oxo-λ⁶-sulfanylidene]-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea (1.0 g, 2.59 mmol) in THF (50 mL). To the stirred solution was added PBr₃ (702 mg, 2.59 mmol) in portions. The resulting solution was stirred for 3 h at RT. The solids were collected by filtration. This resulted in 500 mg (43%) of the title compound as a white solid. MS-ESI: 449/411 (M+1).

Intermediate 85

N′-(tert-butyldimethylsilyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-6-sulfonimidamide Step 1: 6-Bromo-2-methyl-1,2,3,4-tetrahydroisoquinoline

Into a 250-mL round-bottom flask, was placed 6-bromo-1,2,3,4-tetrahydroisoquinoline (6.0 g, 28.3 mmol) in MeOH (100 mL) under N₂. To the stirred solution was added HCHO (1.02 g, 34 mmol) in portions at RT. The resulting solution was stirred for 4 h, then NaBH₃CN (3.56 g, 56.6 mmol) was added in portions at RT. The resulting solution was stirred overnight at RT. The reaction was then quenched by the addition of water (100 mL) and extracted with 3×150 mL ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was eluted from a silica gel column with acetate/petroleum ether (1:1). This resulted in 5 g (78.2%) of the title compound as a white solid. MS-ESI: 226/228 (M+1).

Steps 2-5 used similar procedures for converting compound 185″ to Intermediate 173″ shown in Scheme 44 to afford Intermediate 85 from compound 229. MS-ESI: 238 (M+1).

Intermediate 86

N′-(tert-butyldimethylsilyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonimidamide Step 1: 1-(3,4-Dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1,2,3,4-tetrahydroisoquinoline (8.0 g, 60.1 mmol) and 2,2,2-trifluoroacetic anhydride (25.2 g, 120 mmol). The resulting solution was stirred for 12 h at RT. The reaction was then quenched by the addition of 100 mL of water/ice. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 10 g (72.6%) of the title compound as a yellow solid. MS-ESI: 230 (M+1).

Steps 2-3 used similar procedures for converting compound 158″ to Intermediate 61 shown in Scheme 38 to afford compound 236″ from compound 234″. MS-ESI: 309 (M+1).

Step 4: 1,2,3,4-Tetrahydroisoquinoline-7-sulfonamide

Into a 100-mL round-bottom flask, was placed 2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (8.0 g, 26 mmol) in ethanol (12 mL) and H₂O (60 mL). To the stirred solution was added KOH (7.28 g, 123 mmol) in one portion at RT. The resulting solution was stirred for 12 h at RT. The resulting mixture was concentrated. The crude product was applied onto a silica gel column with DCM/MeOH (10:1). This resulted in 5.0 g (90.8%) of the title compound as a light yellow solid.

Step 5 used similar procedures for converting compound 228″ to compound 229″ shown in Scheme 53 to afford compound 238″ from compound 237″. MS-ESI: 227 (M+1).

Steps 6-7 used similar procedures for converting compound 148″ to intermediate 59 shown in Scheme 36 to afford intermediate 86 from compound 238″. MS-ESI: 340 (M+1).

Intermediate 87

N′-(tert-butyldimethylsilyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonimidamide Step 1: 4-((Dimethylamino)methyl)-2-methoxybenzenesulfonamide

Into a 50-mL round-bottom flask, was placed 4-[(dimethylamino)methyl]-2-fluorobenzene-1-sulfonamide (1 g, 4.31 mmol) and DMF (10 mL, 0.14 mmol). Then to the above was added sodium methoxide (2.16 g, 40 mmol). The resulting solution was stirred for 12 h at RT. The reaction was then quenched by the addition of 5.0 mL of water. The residue was eluted from a C18 column with ACN:H₂O (3:7). This resulted in 800 mg (76.1%) of the title compound as a yellow solid. MS-ESI: 245 (M+1).

Steps 2-3 used similar procedures for converting compound 148″ to intermediate 59 shown in Scheme 36 to afford intermediate 87 from compound 240″. MS-ESI: 358 (M+1).

Intermediate 88

N′-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-3-fluorothiophene-2-sulfonimidamide Step 1: (4-Fluorothiophen-2-yl)methanol

Into a 1000-mL round-bottom flask, was placed methyl 4-fluorothiophene-2-carboxylate (10 g, 62.4 mmol) in ethanol (300 mL). Then to the above solution was added NaBH₄ (4.62 g, 125 mmol) in portions at 0° C. in an ice/ethanol bath. The resulting solution was stirred for 30 min at 0° C. and then the reaction solution was allowed to react for an additional 16 h at RT. The reaction was then quenched by the addition of 50 mL of water. Then the mixture was concentrated and extracted with 3×100 mL of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 6.4 g (77.6%) of the title compound as white oil. MS-ESI: 133 (M+1)

Step 2: 2-(Bromomethyl)-4-fluorothiophene

Into a 250-mL round-bottom flask, was placed (4-fluorothiophen-2-yl)methanol (8.5 g, 64.3 mmol) in DCM (70 mL). To the stirred solution was added PBr₃ (19.2 g, 70.8 mmol) dropwise at 0° C. in an ice/ethanol bath. The resulting solution was stirred for 30 min at 0° C. The resulting solution was allowed to react for an additional 12 h at RT. The reaction was then quenched by the addition of 50 mL of water. Then the mixture was concentrated and extracted with 3×100 mL of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (15/85). This resulted in 7.0 g (55.8%) of the title compound as yellow oil. MS-ESI: 194/196 (M+1).

Step 3: 1-(4-Fluorothiophen-2-yl)-N,N-dimethylmethanamine

Into a 250-mL round-bottom flask, was placed 2-(bromomethyl)-4-fluorothiophene (7.4 g, 37.9 mmol) in CHCl₃ (50 mL). To the above solution was added butoxytributyl-l4-azane sulfate (6.76 g, 19 mmol) and DMA (37 mL, 425 mmol) with stirring at RT. The resulting solution was stirred for 2 h at 60° C. The reaction was then quenched by the addition of 50 mL of water. Then the mixture was concentrated and extracted with 3×100 mL of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (17/83). This resulted in 6.0 g (99.5%) of the title compound as a yellow solid. MS-ESI: 160 (M+1).

Step 4: Lithium 5-((dimethylamino)methyl)-3-fluorothiophene-2-sulfinate

Into a 500-mL 3-necked round-bottom flask purged with and maintained under nitrogen, was placed a solution of [(4-fluorothiophen-2-yl)methyl]dimethylamine (6.2 g, 38.9 mmol) in THF (60 mL). This was followed by the addition of n-BuLi/THF (18.7 mL, 2.5 M) dropwise with stirring at −78° C. in a liquid nitrogen/ethanol bath. The resulting solution was stirred for 30 min at −78° C. To the above SO₂(g) was introduced into the reaction solution at −78° C. The resulting solution was allowed to react for an additional 2 h at RT. The resulting mixture was concentrated. This resulted in 10 g (crude) of the title compound as a yellow solid. MS-ESI: 222 (M−1).

Step 5: 5-((Dimethylamino)methyl)-3-fluorothiophene-2-sulfonyl chloride

Into a 500-mL round-bottom flask, was placed a solution of 5-[(dimethylamino)methyl]-3-fluorothiophene-2-sulfinic acid (10 g, 44.8 mmol) in THF (100 mL). To the above solution was added NCS (7.18 g, 53.8 mmol). The resulting solution was stirred for 30 min at 0° C. and then allowed to react for an additional 2 h at RT. This reaction was used for next step without purification.

Step 6: 5-((Dimethylamino)methyl)-3-fluorothiophene-2-sulfonamide

Into a 500-mL round-bottom flask, was placed a solution of 5-[(dimethylamino)methyl]-3-fluorothiophene-2-sulfonyl chloride (10 g, 38.8 mmol) in THF (100 mL). To the above NH₃ (g) was introduced at RT. The resulting solution was stirred for 30 min at RT. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (60/40). This resulted in 2.1 g (22.7%) of the title compound as yellow oil. MS-ESI: 239 (M+1).

Step 7: N-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-3-fluorothiophene-2-sulfonamide

Into a 100-mL round-bottom flask, was placed a solution of 5-[(dimethylamino)methyl]-3-fluorothiophene-2-sulfonamide (1.8 g, 7.55 mmol) in THF (30 mL) under N₂. To the above solution was added NaH (60% wt. oil dispersion, 640 mg, 15 mmol) with stirring at 0° C. The resulting solution was stirred for 5 min at 0° C. This was followed by the addition of TBSCl (1.37 g, 9.09 mmol) at 0° C. The resulting solution was allowed to react for an additional 15 h at RT. The reaction was then quenched by the addition of 20 mL of water. Then the mixture was concentrated and extracted with 3×100 mL of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 2.0 g (75.2%) of the title compound as yellow oil. MS-ESI: 353 (M+1).

Step 8: N-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-3-fluorothiophene-2-sulfonimidoyl chloride

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of PPh₃Cl₂ (29.5 g, 88.7 mmol) in CHCl₃ (50 mL). To the above solution was added DIEA (17.2 g, 133 mmol) dropwise in an ice/water bath. The solution was stirred at RT for 20 minutes. This was followed by the addition of N-(tert-butyldimethylsilyl)-5-[(dimethylamino)methyl]-3-fluorothiophene-2-sulfonamide (15.7 g, 44.4 mmol) in CHCl₃ (30 mL) at 0° C. The resulting solution was allowed to react for an additional 30 min at 0° C. Then the reaction solution was used for next step without purification.

Step 9: N′-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-3-fluorothiophene-2-sulfonimidamide

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [(tert-butyldimethylsilyl)imino](chloro)[5-[(dimethylamino)methyl]-3-fluorothiophen-2-yl]-λ⁶-sulfanone (16.5 g, 44.4 mmol) in CHCl₃ (80 mL). To the above NH₃(g) was introduced at 0° C. for 15 min. The resulting solution was stirred for 15 min at 0° C. and then allowed to react for an additional 15 h at RT. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (60/40). This resulted in 5.8 g (37.2%) of the title compound as a yellow solid. MS-ESI: 352(M+1).

Intermediate 112

N′-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide Step 1: 2-(2-Hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 250-mL round-bottom flask, was placed a solution of tert-butyl 2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidoylcarbamate (3.21 g, 10 mmol) in HCl/dioxane (4 M, 50 mL). The resulting solution was stirred for 1 h at RT. The solution was concentrated to give the title compound (3.2 g, crude, yellow oil). MS-ESI: 222 (M+1).

Step 2: N′-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 250-mL round-bottom flask, was placed 2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (3.2 g crude, 10 mmol) in THF (100 mL), DIEA (3.87 g, 30 mmol) was added in at RT. Then TBSCl (3.0 g, 20 mmol) was added to the solution in portions. The resulting solution was stirred for 16 h at RT. The solution was concentrated and the crude product was purified by silica gel column with ethyl acetate/petroleum ether (1:1) to give the title compound (2.3 g, yield 70%, yellow solid). MS-ESI: 336 (M+1).

Intermediate 113

2-(2-Hydroxypropan-2-yl)-N-methylthiazole-5-sulfonimidamide Step 1: Tert-butyl (chloro(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ⁶-sulfaneylidene)carbamate

Into a 1-L round-bottom flask, was placed tert-butyl N-[[2-(2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]sulfinyl]carbamate (100 g, 326 mmol) in ACN (500 mL). To the stirred solution was added NCS (65.4 g, 49 mmol). The resulting solution was stirred for 2 h at RT. The resulted solution was concentrated. This resulted in 120 g crude title compound as yellow oil.

Step 2: Tert-((2-(2-hydroxypropan-2-yl)thiazol-5-yl)(methylamino)(oxo)-λ⁶-sulfaneylidene)carbamate

Into a 250-mL round-bottom flask, was placed tert-butyl N-[chloro[2-(2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]oxo-λ⁶-sulfanylidene]carbamate (10 g, 29.3 mmol) in THF (100 mL). To the stirred solution was added CH₃NH₂ (1.82 g, 58.6 mmol). The resulting solution was stirred for 2 h at RT. The resulted solution was concentrated. The residue was eluted from silica gel with ethyl acetate/petroleum ether (1:1). This resulted in 6.1 g (62%) of the title compound as a yellow solid. MS-ESI: 336 (M+1).

Step 3: 2-(2-Hydroxypropan-2-yl)-N′-methylthiazole-5-sulfonimidamide

Into a 100-mL round-bottom flask, was placed tert-butyl((2-(2-hydroxypropan-2-yl)thiazol-5-yl) (methylamino)(oxo)-λ⁶-sulfaneylidene)carbamate (3.0 g, 8.94 mmol) in HCl (gas) in 1,4-dioxane (8.0 mL, 26.3 mmol) in one portion at RT. The resulting solution was stirred for 60 min at RT. The resulting mixture was concentrated under vacuum. This resulted in 2.10 g crude title compound as a yellow solid. MS-ESI: 236 (M+1).

The schemes below illustrate the synthesis of Intermediates 89-96, 101-104, 114-117A, and 118″-126″, which are isocyanate and precursors thereof as well as other intermediates:

Intermediate 89

7-Nitro-6-vinyl-1H-indazole Step 1: 7-Nitro-1H-indazol-6-ol

Into a 25-mL round-bottom flask, was placed 1H-indazol-6-ol (500 mg, 3.73 mmol). This was followed by the addition of H₂SO₄ (5.0 mL) in several batches at 0° C. To this was added KNO₃ (377 mg, 3.73 mmol) in portions at 0° C. The resulting solution was stirred for 30 min at 0° C. in a water/ice bath. The reaction was then quenched by the addition of 50 mL of water/ice. The solids were collected by filtration. This resulted in 350 mg (52.4%) of the title compound as a brown solid. MS-ESI: 180 (M+1).

Step 2: 7-Nitro-1H-indazol-6-yl trifluoromethanesulfonate

Into a 50-mL round-bottom flask, was placed 7-nitro-1H-indazol-6-ol (350 mg, 1.95 mmol) in DCM (10 mL), TEA (593 mg, 5.86 mmol), Tf₂O (717 mg, 2.54 mmol). The resulting solution was stirred for 16 h at RT. The resulting solution was diluted with 20 mL of H₂O. The resulting solution was extracted with 3×20 mL of ethyl acetate dried over anhydrous sodium sulfate and concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 80 mg (13.2%) of the title compound as a yellow solid. MS-ESI: 312 (M+1).

Step 3: 7-Nitro-6-vinyl-1H-indazole

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 7-nitro-1H-indazol-6-yl trifluoromethanesulfonate (100 mg, 0.32 mmol) in dioxane (10 mL) and H₂O (2.0 mL), Cs₂CO₃ (209 mg, 0.64 mmol), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (59.4 mg, 0.39 mmol), Pd(dppf)Cl₂ (23.5 mg, 0.030 mmol). The resulting solution was stirred for 16 h at 90° C. in an oil bath. Then the mixture was concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 50 mg (82.6%) of the title compound as a yellow solid. MS-ESI: 190 (M+1).

Intermediate 90

6-Ethyl-1H-indazol-7-amine Step 4: 6-Ethyl-1H-indazol-7-amine

Into a 50-mL round-bottom flask, was placed 6-ethenyl-7-nitro-1H-indazole (50 mg) in MeOH (10 mL), and Pd/C (10% wt., 5.0 mg). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 12 h at RT under an atmosphere of hydrogen. The Pd/C catalysts were filtered out, the filtrate was concentrated under vacuum. This resulted in 44 mg of the title compound as a yellow solid. MS-ESI: 162 (M+1).

Intermediate 91

6-Ethyl-2-methyl-2H-indazol-7-amine Step 1: 2-Methyl-7-nitro-6-vinyl-2H-indazole

Into a 50-mL round-bottom flask, was placed 6-ethenyl-7-nitro-1H-indazole (380 mg, 2.01 mmol) in acetone (20 mL), KOH (225 mg, 4.02 mmol). This was followed by the addition of MeI (342 mg, 2.41 mmol) dropwise with stirring. The resulting solution was stirred for 1 h at 0° C. in a water/ice bath. The resulting solution was diluted with 20 mL of H₂O. The resulting solution was extracted with 3×30 ml of ethyl acetate dried over anhydrous sodium sulfate and concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 210 mg (51.5%) of 254″ as a yellow solid and 180 mg (44%) of 255″ as a yellow solid. MS-ESI: 208 (M+1).

Step 2: 6-Ethyl-2-methyl-2H-indazol-7-amine

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of N₂, was placed 6-ethenyl-1-methyl-7-nitro-1H-indazole (210 mg, 1.03 mmol) in MeOH (15 mL) and Pd/C (10% wt., 50 mg). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 12 h at RT under an atmosphere of hydrogen. The Pd/C catalysts were filtered out, and the filtrate was concentrated under vacuum. This resulted in 160 mg (88.4%) of the title compound as a yellow solid. MS-ESI:176 (M+1).

TABLE 14 The Intermediates in the following Table were prepared using the similar procedures for converting compound 254″ to Intermediate 91 shown in Scheme 58 from 255″. Intermediate Exact Mass # Structure IUPAC Name [M + H]⁺ Intermediate 92

6-Ethyl-1-methyl- 1H-indazol-7-amine 176

Intermediate 93

2,4,5,6-Tetrahydro-1H-cyclobuta[f]inden-3-amine Step 1: Bicyclo[4.2.0]octa-1(6),2,4-triene-3-carbaldehyde

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-bromobicyclo[4.2.0]octa-1(6),2,4-triene (70 g, 382 mmol) in THF (300 mL). This was followed by the addition of n-BuLi (184 mL, 459 mmol) dropwise with stirring at about −70° C. After addition, the reaction mixture was stirred at this temperature for 30 min. To this solution was added DMF (36.3 g, 497 mmol) dropwise with stirring at −70° C. The resulting solution was stirred for 30 min at −70° C. in a liquid nitrogen bath. The reaction was slowly warmed to RT and then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3×200 ml of DCM. The organic layers combined and dried over anhydrous Na₂SO₄, and then the organic layers was concentrated. This resulted in 50 g (98.9%) of the title compound as light yellow oil. MS-ESI: 133 (M+1).

Step 2: (Z)-3-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)acrylic acid

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed bicyclo[4.2.0]octa-1(6),2,4-triene-3-carbaldehyde (1.7 g, 12.9 mmol) in pyridine (20 mL), propanedioic acid (1.99 g, 19.2 mmol) and piperidine (110 mg, 1.29 mmol). The resulting solution was stirred for overnight at 90° C. in an oil bath. The resulting mixture was concentrated. This resulted in 2.1 g (93.7%) of the title compound as a solid. MS-ESI: 173 (M−1).

Step 3: 3-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)propanoic acid

Into a 250-mL round-bottom flask, was placed 2-(Z or E)-3-[bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl]prop-2-enoic acid (2.1 g, 12.1 mmol) and Pd/C (10% wt., 200 mg). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 12 h at RT under an atmosphere of hydrogen. The Pd/C catalysts were filtered out, the filtrate was concentrated under vacuum. This resulted in 2.1 g (98.9%) of the title compound as a solid. MS-ESI: 175 (M−1).

Step 4: 3-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)propanoyl chloride

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-[bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl]propanoic acid (10 g, 56.8 mmol) in DCM (100 mL). This was followed by the addition of oxalyl chloride (7.2 g, 56.8 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at 0° C. in a water/ice bath. The resulting mixture was concentrated. This resulted in 10 g (90.5%) of the title compound as light yellow oil.

Step 5: 1,2,5,6-Tetrahydro-4H-cyclobuta[f]inden-4-one

Into a 100-mL round-bottom flask, was placed 3-[bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl]propanoyl chloride (5.0 g, 25.7 mmol) in DCM (50 mL). This was followed by the addition of AlCl₃ (3.4 g, 25.7 mmol) in portions at 0° C. for 10 min. The resulting solution was stirred for 1 h at 0° C. in a water/ice bath. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 2×50 mL of DCM. The organic layers combined and dried over anhydrous Na₂SO₄, then concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:20 to 1:15). This resulted in 3.5 g (86.1%) of the title compound as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 7.45 (s, 1H), 7.17 (s, 1H), 3.22 (m, 4H), 3.18-3.00 (m, 2H), 2.73-2.63 (m, 2H).

Step 6: 2,4,5,6-Tetrahydro-1H-cyclobuta[f]indene

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1,2,5,6-tetrahydrocyclobuta[f]inden-4-one (20 g, 126 mmol) in THF (200 mL). This was followed by the addition of BH₃—Me₂S (25.3 mL, 253 mmol, 10 M) dropwise at 0° C. in an ice bath. The resulting solution was stirred for 14 h at 70° C. in an oil bath. The reaction was then quenched by the addition of 20 mL of MeOH. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:100 to 1:50). This resulted in 15 g (82.3%) of the title compound as colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 6.95 (s, 2H), 3.10 (s, 4H), 2.88 (t, J=7.4 Hz, 4H), 2.03 (p, J=7.4 Hz, 2H).

Step 7: 3-Iodo-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene

Into a 500-mL round-bottom flask, was placed acetic acid (100 mL), 2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (15 g, 104 mmol) and NIS (35.1 g, 156 mmol). The resulting solution was stirred for 3 h at 50° C. in an oil bath. The resulting solution was diluted with 200 mL of water. The mixture was extracted with 3×100 mL of DCM. The organic layers combined and dried over anhydrous Na₂SO₄, then concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:100 to 1:80). This resulted in 5.0 g (17.8%) of the title compound as yellow oil.

Step 8: Tert-butyl (2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamate

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-iodo-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (5.0 g, 18.5 mmol) in toluene (100 mL), tert-butyl carbamate (6.5 g, 55.5 mmol), X-phos (900 mg, 1.85 mmol), Pd₂(dba)₃ (800 mg, 0.93 mmol) , t-BuOK (6.2 g, 55.5 mmol). The resulting solution was stirred for 14 h at 100° C. in an oil bath. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:50 to 1:20). This resulted in 3.0 g (83.3%) of the title compound as a white solid. MS-ESI: 260 (M+1).

¹H NMR (300 MHz, CDCl₃) δ 6.72 (s, 1H), 6.13 (br, 1H), 3.26 (d, J=4.5 Hz, 2H), 3.01 (d, J=4.5 Hz, 2H), 2.90 (t, J=7.4 Hz, 2H), 2.75 (t, J=7.4 Hz, 2H), 2.06 (p, J=7.4 Hz, 2H), 1.52 (s, 9H).

Step 9: 2,4,5,6-Tetrahydro-1H-cyclobuta[f]inden-3-amine

Into a 100-mL round-bottom flask, was placed tert-butyl2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-ylcarbamate (3.0 g, 11.6 mmol) in DCM (20 mL), 2,2,2-trifluoroacetic acid (5.0 mL). The resulting solution was stirred for 2 h at RT. The resulting solution was diluted with 50 mL of water. The pH value of the solution was adjusted to 10 with sat. aqueous Na₂CO₃. The resulting solution was extracted with 3×20 mL of DCM. The organic layers combined and dried over anhydrous Na₂SO₄, then concentrated. This resulted in 1.5 g (81.4%) of the title compound as a yellow solid. MS-ESI: 160 (M+1).

Intermediate 94

3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-4-amine Step 1: 8-Nitro-2,3,5,6-tetrahydro-7H-indeno[5,6-b]furan-7-one

Into a 100-mL round-bottom flask, was placed 2H,3H,5H,6H,7H-indeno[5,6-b]furan-7-one (4 g, 23 mmol,) in H₂SO₄ (20 mL). This was followed by the addition of HNO₃ (2.13 g, 23 mmol, 68%) dropwise with stirring at 0° C. in an ice/ethanol bath. The resulting solution was stirred for 1 h at 0° C. The reaction was then quenched by the addition of 200 mL of water/ice. The solids were collected by filtration. This resulted in 4.0 g (79.5%) of the title compound as a light brown solid. MS-ESI: 220 (M+1).

Step 2: 3,5,6,7-Tetrahydro-2H-indeno[5,6-b]furan-8-amine

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 8-nitro-2H,3H,5H,6H,7H-indeno[5,6-b]furan-7-one (4.0 g, 18.3 mmol) in MeOH (50 mL), TsOH (1.0 mL), Pd(OH)₂/C (20% wt., 1 g). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 16 h at RT under an atmosphere of hydrogen. The solids were filtered out. The resulting mixture was concentrated. The residue was dissolved in 50 mL of EA. The resulting mixture was washed with 2×50 ml of NaHCO₃ and 3 ×40 ml of H₂O. The mixture was dried over anhydrous sodium sulfate. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:9). This resulted in 1.1 g (34.4%) of the title compound as a yellow solid. MS-ESI: 176 (M+1).

Step 3: 4-Bromo-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-amine

Into a 50-mL round-bottom flask, was placed 2H,3H,5H,6H,7H-indeno[5,6-b]furan-8-amine (1.1 g, 6.28 mmol) in ACN (30 mL) and NBS (1.34 g , 7.53 mmol). The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:8). This resulted in 83 mg (52%) of the title compound as a yellow solid. MS-ESI: 254 (M+1).

Step 4: 4-Bromo-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan

Into a 50-mL round-bottom flask, was placed 4-bromo-2H,3H,5H,6H,7H-indeno[5,6-b]furan-8-amine (500 mg, 1.97 mmol) in ethanol (15 mL) and acetic acid (3.0 mL, 0.050 mmol). To the above solution was added NaNO₂ (1.36 g, 19.7 mmol) in H₂O (3 mL) dropwise at 0° C. The resulting solution was stirred for 2 h at RT. The resulting solution was diluted with 30 mL of H₂O. The resulting solution was extracted with 3×30 ml of ethyl acetate dried over anhydrous sodium sulfate and concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 100 mg (21.3%) of the title compound as a yellow solid. MS-ESI: 239 (M+1).

Step 5: Tert-butyl (3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-4-yl)carbamate

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-bromo-2H,3H,5H,6H,7H-indeno[5,6-b]furan (120 mg, 0.50 mmol) in toluene (15 mL), t-BuOK (282 mg, 2.51 mmol), tert-butyl carbamate (588 mg, 5.02 mmol), Xphos (47.8 mg, 0.10 mmol), and Pd₂(dba)₃CHCl₃ (104 mg, 0.10 mmol). The resulting solution was stirred for 16 h at 100° C. in an oil bath. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 80 mg (57.9%) of the title compound as a yellow solid. MS-ESI: 276 (M+1).

Step 6: 3,5,6,7-Tetrahydro-2H-indeno[5,6-b]furan-4-amine

Into a 50-mL round-bottom flask, was placed tert-butyl N-[2H,3H,5H,6H,7H-indeno[5,6-b]furan-4-yl] carbamate (80 mg, 0.29 mmol) in DCM (8 mL) and TFA (3.0 mL, 0.030 mmol). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated. The residue was dissolved in 15 mL of DCM. The resulting mixture was washed with 2 ×15 ml of NaOH (aq.). The organic layer was dried with Na₂SO₄ and then concentrated. This resulted in 50 mg (98.2%) of the title compound as a yellow solid. MS-ESI: 176(M+1).

Intermediate 95

Tricyclo[6.2.0.0^(3,6)]deca-1,3(6),7-trien-2-amine Step 1: 2,2′-(1,4-Phenylene)bis(ethan-1-ol)

Into a 1.0-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-[4-(carboxymethyl)phenyl]acetic acid (40 g, 200 mmol) in THF (500 mL). This was followed by the addition of BH₃—Me₂S (60 mL, 600 mmol, 10 M) dropwise with stirring at 0 C. The resulting solution was stirred for 24 h at RT. The reaction was then quenched by the addition of 200 mL of water. The resulting solution was extracted with 2×150 mL of ethyl acetate. The organic layers combined and dried over anhydrous Na₂SO₄, then concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:10 to 1:3). This resulted in 28 g (81.8%) of the title compound as brown oil. MS-ESI: 167 (M+1).

Step 2: 1,4-Bis(2-bromoethyl)benzene

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-[4-(2-hydroxyethyl)phenyl]ethan-1-ol (28 g, 168 mmol) in aq. HBr (300 mL, 40% wt.). The resulting solution was stirred for 5 h at 100° C. in an oil bath. The resulting solution was diluted with 500 mL of water. The resulting solution was extracted with 3×200 mL of DCM. The organic layers combined, then concentrated. This resulted in 40 g (81.4%) of the title compound as a white solid. MS-ESI: 291, 293, 295 (M+1).

Step 3: 1,4-Dibromo-2,5-bis(2-bromoethyl)benzene

Into a 500-mL round-bottom flask, was placed 1,4-bis(2-bromoethyl)benzene (30 g, 103 mmol) in trichloromethane (200 mL). To the above solution was added I₂ (0.78 g, 3.08 mmol), iron powder (0.75 g, 13.4 mmol), Br₂ (41 g, 257 mmol). The resulting solution was stirred for 24 h at RT. The reaction was then quenched by the addition of aqueous Na₂SO₃. The resulting solution was extracted with 3×200 mL DCM and the organic layers was combined and dried over anhydrous Na₂SO₄ then concentrated. This resulted in 40 g (86.6%) of the title compound as a white solid. MS-ESI: 449/451/453 (M+1).

Step 4: Tricyclo[6.2.0.0^(3,6)]deca-1,3(6),7-triene

Into a 1000-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1,4-dibromo-2,5-bis(2-bromoethyl)benzene (40 g, 88.9 mmol) in THF (400 mL). This was followed by the addition of n-BuLi (74.7 mL, 187 mmol, 2.5 M) dropwise with stirring at −78° C. in a liquid nitrogen bath. The resulting solution was stirred for 30 min at −78° C. The reaction was then quenched by the addition of aqueous NH₄Cl (300 ml) and extracted with 2×200 mL of DCMDCM and the organic layers was combined and dried over anhydrous Na₂SO₄ then concentrated. This resulted in 8.0 g (69.1%) of the title compound as a light yellow solid.

Step 5: 2-Iodotricyclo[6.2.0.0^(3,6)]deca-1,3(6),7-triene

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tricyclo[6.2.0.0^(3,6)]deca-1,3(6),7-triene (8 g, 61.45 mmol) in acetic acid (50 mL) and NIS (20.7 g, 92.2 mmol). The resulting solution was stirred for 3 h at 50° C. in an oil bath. The resulting solution was diluted with 100 mL of water. The reaction was then quenched by the addition of aqueous Na₂SO₃. The resulting solution was extracted with 3×50 mL of DCM and the organic layers was combined and dried over anhydrous Na₂SO₄ then concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:100). This resulted in 2.5 g (18.2%) of the title compound as a white solid.

Step 6: Tert-butyl tricyclo[6.2.0.0^(3,6)]deca-1,3(6),7-trien-2-ylcarbamate

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-iodotricyclo[6.2.0.0^(3,6)]deca-1,3(6),7-triene (2.5 g, 9.76 mmol) in toluene (50 mL). To the stirred solution was added tert-butyl carbamate (3.43 g, 29.3 mmol), Pd₂(dba)₃ (447 mg, 0.49 mmol), Xphos (466 mg, 0.98 mmol), and t-BuOK (3.29g, 29.3 mmol). The resulting solution was stirred for 14 h at 100° C. in an oil bath. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:50 to 1:30). This resulted in 1.5 g (62.6%) of the title compound as a light yellow solid. MS-ESI: 246 (M+1).

Step 7: Tricyclo[6.2.0.0^(3,6)]deca-1,3(6),7-trien-2-amine

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-[tricyclo[6.2.0.0^(3,6)]deca-1,3(6),7-trien-2-yl]carbamate (1.5 g, 6.1 mmol) in DCM (20 mL) and 2,2,2-trifluoroacetic acid (4.0 mL). The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated. This resulted in 800 mg (90.1%) of the title compound as a brown solid. MS-ESI: 146 (M+1).

Intermediate 96

3-Amino-2,4-diisopropylbenzonitrile Step 1: 3-Amino-2,4-dibromo-6-chlorobenzonitrile

Into a 500-mL round-bottom flask, was placed 5-amino-2-chlorobenzonitrile (10 g, 65.8 mmol), ACN (200 mL) and NBS (17.6 g, 98.7 mmol). The resulting solution was stirred for 14 h at RT. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:15 to 1:5). This resulted in 18 g of the title compound as a yellow solid. MS-ESI: 310, 312 (M+1).

Step 2: 3-Amino-6-chloro-2,4-di(prop-1-en-2-yl)benzonitrile

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-amino-2,4-dibromo-6-chlorobenzonitrile (15 g, 48 mmol) in dioxane (200 mL) and H₂O (20 mL), 2-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-ylium (17.6 g, 106 mmol), Cs₂CO₃ (47 g, 144 mmol), and Pd(dppf)Cl₂ (1.5 g, 4.8 mmol). The resulting solution was stirred for 14 h at 100° C. in an oil bath. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:0 to 1:25). This resulted in 10 g of the title compound as brown oil. MS-ESI: 233 (M+1).

Step 3: 3-Amino-2,4-diisopropylbenzonitrile

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-amino-6-chloro-2,4-bis(prop-1-en-2-yl)benzonitrile (10 g, 43 mmol) in MeOH (50 mL). Then Pd/C (10% wt., 2.0 g) was added. The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 16 h at RT under an atmosphere of hydrogen. The solids were filtered out. The resulting filtrate was concentrated under vacuum. This resulted in 8.0 g of the title compound as brown oil. MS-ESI: 203 (M+1).

Intermediate 101

8-Amino-1,2,3,5,6,7-hexahydro-s-indacen-1-ol Step 1: 8-Amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of hydrogen, was placed a solution of 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (700 mg, 3.22 mmol) in MeOH (10 mL), and Pd/C (10% wt., 100 mg). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 2 h at RT under an atmosphere of hydrogen. The Pd/C catalysts were filtered out, and the filtrate was concentrated under vacuum. This resulted in 550 mg (91.2%) of the title compound as a yellow oil. MS-ESI: 188 (M+1).

Step 2: 8-Amino-1,2,3,5,6,7-hexahydro-s-indacen-1-ol

Into a 100 mL round-bottom flask, was placed a solution of 8-amino-3,5,6,7-tetrahydro-s-indacen-1 (2H)-one (2.0 g, 10.7 mmol) in ethanol. To this solution was added NaBH₄(1.9 g, 50 mmol) with stirring in portions at 0° C. in an ice bath. The resulting solution was stirred for 16 h at RT. The reaction was quenched by water (10 mL). The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate, and then concentrated under vacuum. This resulted in 1.5 g of the title compound as a yellow solid. MS-ESI: 189 (M+1).

Intermediate 103

4-Amino-1,2,3,5,6,7-hexahydro-s-indacen-1-ol Step 1: 4-Amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of hydrogen, was placed a solution of 4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (3.0 g, 13.8 mmol) in MeOH (30 mL), and Pd/C (10% wt., 500 mg). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 4 h at RT under an atmosphere of hydrogen. The Pd/C catalysts were filtered out, the filtrate was concentrated under vacuum. The residue was eluted from a silica gel column with DCM/MeOH (10:1). This resulted in 2.2 g (85.1%) of the title compound as a white solid. MS-ESI: 187 (M+1).

Step 2: 4-Amino-1,2,3,5,6,7-hexahydro-s-indacen-1-ol

Into a 100-mL round-bottom flask, was placed a solution of 8-amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one (2.0 g, 10.7 mmol) in ethanol (20 mL) and NaBH₄ (1.9 g, 50 mmol). The resulting solution was stirred for 16 h at RT. The reaction was quenched with water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The mixture was concentrated under vacuum. This resulted in 1.36 g of the title compound as a yellow solid. MS-ESI: 190 (M+1).

Intermediate 104

3-(3-(But-3-ynyl)-3H-diazirin-3-yl)propanoic acid Step 1: Methyl 3-oxohept-6-ynoate

Into a 2000-mL 3-neck round-bottom flask purged with and maintained under nitrogen, was placed methyl 3-oxobutanoate (20 g, 172 mmol) in THF (200 mL). To the above solution was added LDA (200 mL, 400 mmol, 2 M) dropwise at −20° C. in a dry ice bath. Then reaction was allowed to react at −20° C. for 30 min. Then 3-bromoprop-1-yne (20.5 g, 172 mmol) was added to the reaction solution in portions at −20° C. The resulting solution was stirred for 3 h at −20° C. in a dry ice bath. The reaction was then quenched by the addition of 500 mL of NH₄Cl solution. The pH value of the solution was adjusted to 3 with HCl (aq). The resulting solution was extracted with 3×200 ml of ethyl acetate and the organic layers was combined and dried over anhydrous Na₂SO₄, then concentrated. This resulted in the title compound (2.0 g, 7.53%) as white oil.

Step 2: Methyl 2-(2-(but-3-ynyl)-1,3-dioxolan-2-yl)acetate

Into a 500-mL round-bottom flask, was placed methyl 3-oxohept-6-ynoate (20 g, 130 mmol) in toluene (200 mL), ethane-1,2-diol (40.2 g, 649 mmol) and TsOH (2.23 g, 13 mmol). The resulting solution was stirred for 6 h at 120° C. in an oil bath. The resulting solution was diluted with 200 mL of Et₂O. The resulting mixture was washed with 3 ×100 ml of NaHCO₃ and 3×100 ml of saturated NaCl solution. The mixture was dried over anhydrous sodium sulfate and concentrated. This resulted in the title compound (20 g, 77.9%) as yellow oil.

Step 3: 2-(2-(But-3-ynyl)-1,3-dioxolan-2-yl)ethanol

Into a 1.0-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 2-[2-(but-3-yn-1-yl)-1,3-dioxolan-2-yl]acetate (90 g, 454 mmol) in THF (300 mL). To this above solution was added LiAlH₄ (17.9 g, 472 mmol) in portions with stirring at 0° C. in an ice/ethanol bath. The resulting solution was stirred for 6 h at RT. The reaction was then quenched by the addition of water/ice. The solids were filtered out. The resulting filtrate was concentrated under vacuum. This resulted in the title compound (80 g crude) and used in the next step directly. MS-ESI: 169 (M−1).

Step 4: 1-Hydroxyhept-6-yn-3-one

Into a 3.0-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-[2-(but-3-yn-1-yl)-1,3-dioxolan-2-yl]ethan-1-ol (80 g, 470 mmol) in THF (1.0 L) and HCl (500 mL). The resulting solution was stirred for 16 h at RT. The resulting solution was diluted with 1.0 L of water. The mixture was extracted with 3×1.0 L of ethyl acetate and the organic layer was combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting filtrate was concentrated under vacuum. The residue was eluted from a silica gel column with DCM/petroleum ether (1:1). This resulted in 20 g of the title compound as a white solid. MS-ESI: 125 (M−1).

Step 5: 2-(3-(But-3-ynyl)diaziridin-3-yl)ethanol

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1-hydroxyhept-6-yn-3-one (20 g, 159 mmol) in DCM (250 mL). To the above solution was introduced NH₃ (g) for 15 min at −40° C. in a liquid nitrogen/ethanol bath. The resulting solution was stirred for 1 h at −40° C. and then allowed to react for 16 h at RT. The resulting mixture was concentrated. This resulted in 18 g (crude) of the title compound as a white solid. MS-ESI: 141 (M+1).

Step 6: 2-(3-(But-3-ynyl)-3H-diazirin-3-yl)ethanol

Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-[3-(but-3-yn-1-yl)diaziridin-3-yl]ethan-1-ol (14.4 g, 114 mmol) in DCM (200 mL), TEA (34.6g, 342 mmol), I₂ (58 g, 228 mmol). The resulting solution was stirred for 4 h at RT. The reaction was then quenched by the addition of Na₂S₂O₃. The resulting mixture was quenched with 100 mL of water. The resulting solution was extracted with 3×300 mL of DCM and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated. This resulted in 6.0 g (38%) of the title compound as a white solid. MS-ESI: 139 (M+1).

Step 7: 3-(But-3-ynyl)-3-(2-iodoethyl)-3H-diazirine

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-[3-(but-3-yn-1-yl)-3H-diazirin-3-yl]ethan-1-ol (5.0 g, 36.2 mmol) in THF (20 mL), imidazole (3.7 g, 54.3 mmol), I₂ (9.18 g, 36.2 mmol), PPh₃ (14.2 g, 54.3 mmol). The resulting solution was stirred for 16 h at RT. The reaction was then quenched by the addition of 20 mL of saturated Na₂S₂O₃ solution. The resulting solution was extracted with 3×50 mL of DCM dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated. This resulted in 5.0 g (crude) of the title compound as a yellow solid. MS-ESI: 248 (M+1).

Step 8: 3-(3-(But-3-ynyl)-3H-diazirin-3-yl)propanenitrile

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-(but-3-yn-1-yl)-3-(2-iodoethyl)-3H-diazirine (5.0 g, 20.2 mmol) in DMF (250 mL), KCN (2.62 g, 40.3 mmol). The resulting solution was stirred for 16 h at 60° C. in an oil bath. The reaction was then quenched by the addition of 20 mL of FeSO₄ solution. The resulting solution was extracted with 3×50 ml of ethyl acetate dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated. This resulted in 2.0 g (crude) of the title compound as a solid. MS-ESI: 148 (M+1).

Step 9: 3-(3-(But-3-ynyl)-3H-diazirin-3-yl)propanoic acid

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-[3-(but-3-yn-1-yl)-3H-diazirin-3-yl]propanenitrile (1.0 g, 3.40 mmol) in MeOH (40 mL), NaOH (272 mg, 6.79 mmol). The resulting solution was stirred for 16 h at 90° C. in an oil bath. The resulting solution was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 400 mg crude (26.6%) of the title compound as yellow oil. MS-ESI: 167 (M+1).

Intermediate 114

3,5-Diisopropyl-1-phenyl-1H-pyrazol-4-amine Step 1: 3,5-Diisopropyl-1-phenyl-1H-pyrazole

Into a 100-mL round-bottom flask, was placed 2-propanol (50 mL), phenylhydrazine (3.81 g, 35.2 mmol) and 2,6-dimethylheptane-3,5-dione (5.0 g, 32.0 mmol). The resulting solution was stirred overnight at 85° C. in an oil bath. The resulting mixture was concentrated. The residue was dissolved in 100 mL of ethyl acetate. The resulting mixture was washed with 50 mL of H₂O. The mixture was dried over anhydrous sodium sulfate and then concentrated. This resulted in 6.9 g (94%) of the title compound as a light yellow oil. MS-ESI: 229 (M+1).

Step 2: 3,5-Diisopropyl-4-nitro-1-phenyl-1H-pyrazole

Into a 100-mL round-bottom flask, was placed 1-phenyl-3,5-bis(propan-2-yl)-1H-pyrazole (6.9 g, 30 mmol) in Ac₂O (50 mL). This was followed by the addition of HNO₃ (4.07 mL, 91 mmol) dropwise with stirring at 0° C. in 10 min. The resulting solution was stirred for overnight at RT. The residue was dissolved in 150 mL of ethyl acetate. The resulting mixture was washed with 2×100 mL of H₂O. The mixture was dried over anhydrous sodium sulfate and then concentrated. This resulted in 3.7 g (44.8%) of the title compound as yellow oil. MS-ESI: 274 (M+1).

Step 3: 3,5-Diisopropyl-1-phenyl-1H-pyrazol-4-amine

Into a 250-mL round-bottom flask, was placed 4-nitro-1-phenyl-3,5-bis(propan-2-yl)-1H-pyrazole (3.7 g, 13.5 mmol) in MeOH (100 mL), to the stirred solution was added Pd/C (10% wt., 400 mg). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred overnight at RT under an atmosphere of hydrogen. The Pd/C catalysts were filtered out, the filtrate was concentrated under vacuum. This resulted in 2.7 g (82%) of the title compound as a light yellow oil. MS-ESI: 244 (M+1).

Intermediate 116

1,2,3,6,7,8-Hexahydro-as-indacen-4-amine Step 1: 4-Nitro-1,6,7,8-tetrahydro-as-indacen-3(2H)-one (308) and 5-nitro-1,6,7,8-tetrahydro-as-indacen-3(2H)-one (309″)

Into a 250-mL round-bottom flask was placed a solution of 1,6,7,8-tetrahydro-as-indacen-3(2H)-one (Cpd 307″ was isolated from 113″ in Scheme 23 by chromatography) (9.8 g, 46.5 mmol) in H₂SO₄ (50 mL). Then HNO₃ (5.85 g, 92.9 mmol) was added dropwise over 10 min at 0° C. The resulting solution was stirred for 1 h at 0° C. The reaction mixture was slowly added to a mixture of water/ice (100 mL) and DCM (50 mL) with ice bath cooling. The organic layer was collected, dried over Na₂SO₄ and concentrated under vacuum. This resulted in 11 g (89%) of a mixture of cpd 308″ and cpd 309″ as a yellow solid. The mixture was monitored by TLC (ethyl acetate/petroleum ether=1/10, R_(f)=0.4),

Step 2: 1,2,3,6,7,8-hexahydro-as-indacen-4-amine (116)

Into a 100-mL round-bottom flask was placed a solution of the mixture of 4-nitro-1,6,7,8-tetrahydro-as-indacen-3 (2H)-one and 5-nitro-1,6,7,8-tetrahydro-as-indacen-3 (2H)-one (2.17 g, 10 mmol) in MeOH (30 mL). To the solution was added MSA (1.15 g, 12 mmol). Then Pd(OH)₂/C (20% wt., 550 mg) was added. The flask was evacuated and filled three times with hydrogen. The resulting mixture was stirred for 16 h at RT under hydrogen (50 psi). The solids were filtered out and washed with MeOH. The MeOH filtrate and wash was diluted with water (50 mL) and the pH was adjusted to 10.6 with 2 N NaOH. The resulting mixture was filtered and the crude solids were recrystallized from MeOH/water (9:1) with heating. This resulted in 1.38 g (80%) of the title compound as an off-white solid. MS-ESI: 174 (M+1).

Intermediate 117

1,2,3,5,6,7-Hexahydro-s-indacen-3,3,5,5-d₄-4-amine Step 1: 5-Bromo-2,3-dihydro-1H-indene-1,1-d₂

Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of LiAlD4 (1.57 g, 37 mmol) in Et₂O (150 mL). This was followed by the addition of AlCl₃ (10.1 g, 76 mmol) in portions at 0° C. in 5 min. To this was added 5-bromo-2,3-dihydro-1H-inden-1-one (4.0 g, 19 mmol) in portions at 0° C. in 5 min. The resulting solution was stirred for 4 h at RT. The reaction mixture was cooled to 0° C. with a water/ice bath. The reaction was then quenched by careful addition of 10 mL of water. The solids were filtered out. The resulting solution was extracted with 3×100 mL of ethyl acetate and concentrated under vacuum. This resulted in 3.5 g (93%) of the title compound as brown oil. MS-ESI: 199/201 (M+1).

Step 2: Tert-butyl (E)-3-(2,3-dihydro-1H-inden-5-yl-1,1-d₂)acrylate

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 5-bromo-2,3-dihydro-1H-indene-1,1-d₂ (7.0 g, 35 mmol) in DMF (80 mL), to the stirred solution was added tris(4-methylphenyl)phosphane (1.07 g, 3.52 mmol), tert-butyl prop-2-enoate (4.0 mL), triethylamine (5.0 mL) and Pd(OAc)₂ (395 mg, 1.76 mmol). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The residue was eluted from a silica gel column with DCM/petroleum ether (1:1). This resulted in 5.7 g (66%) of the title compound as light yellow oil. MS-ESI: 247 (M+1).

Step 3: Tert-butyl 3-(2,3-dihydro-1H-inden-5-yl-1,1-d₂)propanoate

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl (E)-3-(2,3-dihydro-1H-inden-5-yl-1,1-d₂)acrylate (5.8 g, 24 mmol) in MeOH (40 mL), to the stirred solution was added Pd/C (580 mg, 10% wt.). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 1 h at RT under an atmosphere of hydrogen. The Pd/C catalysts were filtered out, the filtrate was concentrated under vacuum. This resulted in 5.7 g (98%) of the title compound as colorless oil. MS-ESI: 249 (M+1).

Step 4: 3-(2,3-Dihydro-1H-inden-5-yl-1,1-d₂)propanoic acid

Into a 100-mL round-bottom flask, was placed a solution of tert-butyl 3-(2,3-dihydro-1H-inden-5-yl-1,1-d₂)propanoate (4.3 g, 17.3 mmol) in DCM (50 mL), to the stirred solution was added CF₃COOH (5.5 mL, 74 mmol). The resulting solution was stirred for overnight at RT. The resulting mixture was concentrated under vacuum. This resulted in 3.1 g (93%) of the title compound as an off-white solid. MS-ESI: 191 (M−1).

Step 5: 3-(2,3-Dihydro-1H-inden-5-yl-1,1-d₂)propanoyl chloride

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(2,3-dihydro-1H-inden-5-yl-1,1-d₂)propanoic acid (9.0 g, 41.7 mmol) in DCM (40 mL). This was followed by the addition of oxalic dichloride (8.0 mL) at 0° C. To this was added DMF (0.5 mL) at 0° C. The resulting solution was stirred for 3 h at RT. The resulting mixture was concentrated under vacuum. This resulted in 4.0 g (41%) of the title compound as brown oil.

Step 6: 3,5,6,7-Tetrahydro-s-indacen-1(2H)-one-7,7-d₂

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(2,3-dihydro-1H-inden-5-yl-1,1-d₂)propanoyl chloride (3.9 g, 18 mmol) in DCE (40 mL). This was followed by the addition of AlCl₃ (3.3 g, 25 mmol) in portions at 0° C. in 2 min. The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 200 mL of water/ice. The resulting solution was extracted with 3×50 mL of DCM and the organic layers combined and dried over anhydrous sodium sulfate. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (2:100). This resulted in 1.5 g (46%) of the title compound as an off-white solid. MS-ESI: 175 (M+1).

Step 7: 8-Nitro-3,5,6,7-tetrahydro-s-indacen-1(2H)-one-7,7-d₂ (Cpd 318″, major) and 4-Nitro-3,5,6,7-tetrahydro-s-indacen-1(2H)-one-7,7-d₂ (Cpd 317″, minor)

Into a 25-mL round-bottom flask, was placed 3,5,6,7-tetrahydro-s-indacen-1(2H)-one-7,7-d₂ (120 g). This was followed by the addition of H₂SO₄ (8.0 mL) at 0° C. To this was added HNO₃ (2.0 mL) at 0° C. in 2 min. To the mixture was added H₂SO₄ (2.0 mL) at 0° C. in 2 min. The resulting solution was stirred for 1 h at 0° C. The reaction was then quenched by the addition of water/ice. The resulting solution was extracted with 3×50 mL of ethyl acetate dried in an oven under reduced pressure. The residue was separated on silica gel eluted with ethyl acetate/petroleum ether (3:100). This resulted in 870 mg of cpd 318″ and 290 mg of cpd 317″, both as yellow solids. Cpd 317″: ¹H NMR (300 MHz, CDCl₃) δ 7.83 (s, 1H), 3.55-3.45 (m, 2H), 3.42 (t, J=7.6 Hz, 2H), 2.84-2.74 (m, 2H), 2.22 (t, J=7.6 Hz, 2H). Cpd 318″: ¹H NMR (300 MHz, CDCl₃) δ 7.46 (s, 1H), 3.20-3.00 (m, 4H), 2.83-2.73 (m, 2H), 2.20 (t, J=7.5 Hz, 2H).

Step 8: 8-Amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one-7,7-d₂

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 8-nitro-3,5,6,7-tetrahydro-s-indacen-1(2H)-one-7,7-d₂ (870 mg) in MeOH (100 mL), to the stirred solution was added Pd/C (87 mg, 10% wt.). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 1 h at RT under an atmosphere of hydrogen. The Pd/C catalysts were filtered out, the filtrate was concentrated under vacuum. This resulted in 700 mg of the title compound as a yellow solid. MS-ESI: 190 (M+1).

Step 9: 1,2,3,5,6,7-Hexahydro-s-indacen-3,3,5,5-d₄-4-amine

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of LiAlD₄ (160 mg, 3.8 mmol) in Et₂O (40 mL). This was followed by the addition of AlCl₃ (634 mg, 4.8 mmol) in portions at 0° C. in 2 min. To this solution was added 8-amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one-7,7-d₂ (600 mg, 3.17 mmol) at 0° C. The resulting solution was stirred for 4 h at RT. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was diluted with 20 mL of EtOAc. The solids were filtered out. The resulting solution was extracted with 3×50 mL of ethyl acetate dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (5:1). This resulted in 470 mg (78%) of the Intermediate 117 as a yellow solid. MS-ESI: 178 (M+1).

Intermediate 117A

1,2,3,5,6,7-hexahydro-s-indacen-1,1,7,7-d₄-4-amine

Intermediate 117A was prepared starting from compound 317″ and using the same procedure as shown in scheme 73 above for converting compound 318″ to intermediate 117. MS-ESI: 178 (M+1).

TABLE 15 The Intermediates in the following Table were prepared using similar procedure as shown in Scheme 30 above for converting compound 130″ to Intermediate 44. Intermediate # Structure IUPAC Name Intermediate 118″

6-Ethyl-7-isocyanato-1H-indazole Intermediate 119″

6-Ethyl-7-isocyanato- 1-methyl-1H-indazole Intermediate 120″

3-Isocyanato-2,4,5,6- tetrahydro-1H-cyclobuta[f]indene Intermediate 121″

4-Isocyanato-3,5,6,7- tetrahydro-2H-indeno[5,6-b]furan Intermediate 122″

2-Isocyanatotricyclo [6.2.0.03,6]deca-1,3(6),7-triene Intermediate 123″

8-Isocyanato-2,3,6,7- tetrahydros-indacen-1(5H)-one Intermediate 124″

4-Isocyanato-2,3,6,7- tetrahydros-indacen-1(5H)-one Intermediate 125″

4-isocyanato-1,2,3,5,6,7- hexahydro-s-indacene-3,3,5,5-d₄ Intermediate 126″

4-isocyanato-1,2,3,5,6,7- hexahydro-s-indacene-1,1,7,7-d₄

Schemes below the synthesis of sulfonimidamide Intermediates 118-123.

Intermediate 118

N-(tert-butyldimethylsilyl)-6-isopropylpyridine-3-sulfonimidamide

Steps 1-4 used similar procedures for converting compound 245″ to Intermediate 88 shown in Scheme 56 to afford Intermediate 118 from compound 322″. MS-ESI: 314 (M+1).

Intermediate 119

Step 1: 4-Amino-3-fluoro-N-methylbenzamide

Into a 500 mL round-bottom flask were added 4-amino-3-fluorobenzoic acid (15 g, 97 mmol) and DMF (100 mL) at RT. To the stirred solution was added HATU (74 mg, 0.19 mmol) and DIEA (25 mg, 0.19 mmol) at 0° C. To the above mixture was added MeNH₂/THF (2M, 97 mL, 194 mmol) in one portion at 0° C. The resulting mixture was stirred for additional 2 h at RT. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted from silica gel column with petroleum ether/EtOAc (1:1) to afford the title compound (16 g, 98%) as yellow oil. MS-ESI: 169 (M+1).

Steps 2-3 used similar procedures for converting compound 27 to Intermediate 29 shown in Scheme 9 to afford compound 329″ from compound 327″. MS-ESI: 233 (M+1).

Step 4: 2-Fluoro-4-((methylamino)methyl)benzenesulfonamide

Into a 250-mL round-bottom flask were placed 3-fluoro-N-methyl-4-sulfamoylbenzamide (1.2 g) in THF (40 mL) at 0° C. To the stirred solution was added LiAlH₄ (543 mg, 14 mmol) in portions at 0° C. under nitrogen atmosphere. The resulting mixture was stirred overnight at 70° C. The reaction was quenched with water (2 mL). The resulting mixture was filtered, the filter cake was washed with EtOAc (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc/MeOH=25:1) to afford the title compound (800 mg, 77%) as a white solid. MS-ESI: 219 (M+1).

Step 5: Tert-butyl (3-fluoro-4-sulfamoylbenzyl)(methyl)carbamate

Into a 100-mL round-bottom flask were placed 2-fluoro-4-[(methylamino)methyl]benzene-1-sulfonamide (800 mg, 3.7 mmol) in THF (20 mL) at 0° C. To a stirred solution was added (Boc)₂O (1.5 g, 6.89 mmol) in portions at 0° C. The resulting mixture was stirred for 2 h at RT and concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 1:1) to afford the title compound (900 mg, 77%) as a white solid. MS-ESI: 319 (M+1).

Steps 6-7 used similar procedures for converting compound 248″ to Intermediate 88 shown in Scheme 56 to afford Intermediate 119 from compound 331″. MS-ESI: 432 (M+1).

Intermediate 120

N′-(tert-butyldimethylsilyl)-4-((dimethylamino)methyl)-3-fluorobenzenesulfonimidamide Step 1: 1-(2-Fluoro-4-nitrophenyl)-N,N-dimethylmethanamine

Into a 250-mL round-bottom flask, was placed a solution of 1-(bromomethyl)-2-fluoro-4-nitrobenzene (8.0 g, 34 mmol) in MeOH (50 mL). This was followed by the addition of dimethylamine (2 M, 21 mL) dropwise with stirring at 0° C. in 5 min. The resulting solution was stirred for 4 h at RT. The resulting mixture was concentrated under vacuum. This resulted in 7.0 g crude title compound as yellow oil. MS-ESI: 199 (M+1).

Step 2: 4-((Dimethylamino)methyl)-3-fluoroaniline

Into a 100-mL round-bottom flask, was placed the solution of [(2-fluoro-4-nitrophenyl)methyl]dimethylamine (7.0 g, 35 mmol) in AcOH (20 mL), to the stirred solution was added iron powder (10 g, 179 mmol). The resulting solution was stirred for 16 h at RT. The solids were filtered out. The resulting filtrate was concentrated under vacuum. The residue was eluted from a silica gel column with DCM/MeOH (9:1). This resulted in 6.5 g crude title compound as yellow oil. MS-ESI: 169 (M+1).

Steps 3-4 used similar procedures for converting compound 145″ to compound 147″ shown in Scheme 36 to afford compound 337″ from compound 335″. MS-ESI: 233 (M+1).

Steps 5-6 used similar procedures for converting compound 148″ to Intermediate 59 shown in Scheme 36 to afford Intermediate 120 from compound 337″. MS-ESI: 233 (M+1).

Intermediate 121

N′-(tert-butyldimethylsilyl)-4-isopropylthiophene-2-sulfonimidamide

Steps 1-2 used similar procedures for converting compound 158″ to intermediate 61 shown in Scheme 38 to afford compound 341″ from compound 339″. MS-ESI: 221 (M+1).

Step 3 used similar procedures for converting compound 147″ to compound 148″ shown in Scheme 36 to afford compound 342″ from compound 341″. MS-ESI: 221 (M+1).

Step 4: 4-Isopropylthiophene-2-sulfonamide

Into a 250-mL round-bottom flask, was placed the solution of 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (1.5 g, 6.79 mmol) in DCM (20 mL). To the stirred solution was added TFA (3.9 g, 34 mmol) and Et₃SiH (2.32 g, 20 mmol). The result solution was stirred overnight at RT. The mixture was concentrated under vacuum. The residue was eluted from silica gel column with a gradient of ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in 1.1 g (79%) of the title compound as a light yellow solid. MS-ESI: 206 (M+1).

Steps 5-6 used similar procedures for converting compound 148″ to Intermediate 59 shown in Scheme 36 to afford Intermediate 121 from compound 344″. MS-ESI: 319 (M+1).

Intermediate 122

N-(tert-butyldimethylsilyl)-4-(1-methylpyrrolidin-2-yl)b enzenesulfonimidamide Step 1: 2-(4-Bromophenyl)-1-methylpyrrolidine

Into a 100-mL round-bottom flask, was placed 2-(4-bromophenyl)pyrrolidine (3.0 g, 13.3 mmol) in HCHO (3.23 g, 37% wt.), to the stirred solution was added NaBH₃CN (2.5 g, 40 mmol). The resulting solution was stirred for 12 h at RT and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 2.8 g (88%) of the title compound as a light yellow solid. MS-ESI: 240/242 (M+1).

Steps 2-6 used similar procedures for converting compound 245″ to Intermediate 88 shown in Scheme 56 to afford Intermediate 122″ from compound 347″. MS-ESI: 354 (M+1).

Intermediate 123

N-(tert-butyldimethylsilyl)-2-(2-methyl-1,3-dioxolan-2-yl)thiazole-5-sulfonimidamide Step 1: 2-(2-Methyl-1,3-dioxolan-2-yl)thiazole

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1-(1,3-thiazol-2-yl)ethan-1-one (27 g, 212 mmol) in toluene (300 mL), to the stirred solution was added TsOH (2.0 g, 11.6 mmol) and ethane-1,2-diol (40 g, 644 mmol). The resulting solution was stirred for 14 h at 110° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:20 to 1:10). This resulted in 36 g (99%) of the title compound as brown oil. MS-ESI: 172 (M+1).

Steps 2-5 used similar procedures for converting compound 245″ to Intermediate 88 shown in Scheme 56 to afford Intermediate 123 from compound 353″. MS-ESI: 363 (M+1).

Intermediate 124

N′-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-3-fluoropyridine-2-sulfonimidamide Step 1: 6-Chloro-5-fluoro-N,N-dimethylnicotinamide

To a stirred solution of 6-chloro-5-fluoronicotinic acid (10 g, 49.5 mmol) in THF (150 mL) in a 250-mL round-bottom flask under nitrogen was added HATU (28.2 g, 74.3 mmol), DIEA (12.8 g, 99 mmol) and dimethylamine in THF (2 M, 75 mL, 149 mmol) at RT. The resulting solution was stirred for 16 h at RT. The reaction was quenched with water (400 mL). The resulting solution was extracted with 3×400 mL of EtOAc and the organic layers combined and dried over Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 8.0 g (80%) of the title compound as a white solid. MS-ESI: 203/205 (M+1).

Step 2: 6-(Benzylthio)-5-fluoro-N,N-dimethylnicotinamide

To a stirred solution of 6-chloro-5-fluoro-N,N-dimethylnicotinamide (8.0 g, 39.4 mmol) in dioxane (160 mL) in a 100-mL round-bottom flask under nitrogen was added phenylmethanethiol (9.76 g, 78.8 mmol) and t-BuOK (8.84 g, 78.8 mmol). The resulting solution was stirred for 16 h at 80° C. The resulting mixture was quenched with water (400 mL) and extracted with 3×500 mL of EtOAc. The organic layer was combined and dried over anhydrous Na₂SO₄. The solids were filtered out. The resulting filtrate was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 6.0 g (52%) of the title compound as yellow oil. MS-ESI: 291 (M+1).

Step 3: 1-(6-(Benzylthio)-5-fluoropyridin-3-yl)-N,N-dimethylmethanamine

To a stirred solution of 6-(benzylthio)-5-fluoro-N,N-dimethylnicotinamide (6.0 g, 20.7 mmol) in THF (100 mL) in a 250-mL round-bottom flask under nitrogen was added BH₃ in THF (1 M, 104 mmol, 104 mL) dropwise at 0° C. The resulting solution was stirred for 16 h at RT. The reaction was quenched with MeOH (100 mL). The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 4.4 g (77.1%) of the title compound as a white solid. MS-ESI: 277 (M+1).

Step 4: 5-((Dimethylamino)methyl)-3-fluoropyridine-2-sulfonyl chloride

To a stirred solution of 1-(6-(benzylthio)-5-fluoropyridin-3-yl)-N,N-dimethylmethanamine (4.4 g, 15.9 mmol) in DCM (30 mL), AcOH (15 mL) and H₂O (15 mL) in a 250-mL 3-necked round-bottom flask under nitrogen was introduced Cl₂ gas bubbled at 0° C. for 30 min. Then the resulting solution was stirred for another 30 min at 0° C. The resulting mixture diluted with water (100 mL) and extracted with 3×100 mL DCM. The organic layers were combined and washed with brine (100 mL), then dried over anhydrous Na₂SO₄. This resulted in the title compound in DCM solution which was used for next step directly.

Step 5: 5-((Dimethylamino)methyl)-3-fluoropyridine-2-sulfonamide

To a stirred solution of 5-((dimethylamino)methyl)-3-fluoropyridine-2-sulfonyl chloride (crude) in DCM (300 mL) was introduced NH₃ gas bubbled for 30 min at 0° C. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 1.56 g (42% over two steps) of the title compound as a white solid. MS-ESI: 234 (M+1).

Step 6: N-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-3-fluoropyridine-2-sulfonamide

To a stirred solution of 5-((dimethylamino)methyl)-3-fluoropyridine-2-sulfonamide (233 mg, 1.0 mmol) in THF (10 mL) in a 50-mL round-bottom flask under nitrogen was added NaH (60% dispersion in mineral oil, 120 mg, 3.0 mmol) at 0° C., to this was added TBSCl (227 mg, 1.50 mmol) at 0° C. The resulting solution was stirred for 2 h at RT. The resulting mixture was quenched with 10 mL of water. The resulting solution was extracted with 3×10 mL of EtOAc and dried over anhydrous Na₂SO₄. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 200 mg (57.5%) of the title compound as a yellow solid. MS-ESI: 348 (M+1).

Step 7: N′-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-3-fluoropyridine-2-sulfonimidamide

To a stirred solution of PPh₃Cl₂ (383 mg, 1.15 mmol) in CHCl₃ (10 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added DIEA (371 mg, 2.88 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 10 min at RT. To this was added a solution of N-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-3-fluoropyridine-2-sulfonamide (200 mg, 0.58 mmol) in CHCl₃ (10 mL) dropwise with stirring at 0° C. The resulting solution was allowed to react, with stirring, for an additional 30 min while the temperature was maintained at 0° C. in a water/ice bath. To the above NH₃(g) was bubbled for 10 min at 0° C. The resulting solution was allowed to react, with stirring, for an additional 30 min at RT. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 150 mg (75.0%) of the title compound as an off-white solid. MS-ESI: 347 (M+1).

Intermediate 125

2-(4-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)phenyl)-N,2-dimethylpropanamide Step 1: 2-Methyl-2-(4-sulfamoylphenyl)propanoic acid

To a stirred solution of ethyl 2-methyl-2-(4-sulfamoylphenyl) propanoate (5.42 g, 20.0 mmol) in MeOH (60 mL) in a 250-mL round-bottom flask was added the solution of NaOH (8.0 g, 200 mmol) in water (40 mL) dropwise at RT. The resulting solution was stirred for 2 h at 55° C. and the organic solvent was removed under vacuum. The pH value of the solution was adjusted to 1-2 with HCl (2 M). The resulting solution was extracted with 3×200 mL of DCM and the organic layers were combined and dried over Na₂SO₄, concentrated under vacuum. This resulted in 3.90 g (80.2%) of the title compound as a light yellow solid. MS-ESI: 242 (M−1)

Step 2: N,2-dimethyl-2-(4-sulfamoylphenyl)propanamide

To a stirred solution of 2-methyl-2-(4-sulfamoylphenyl)propanoic acid (2.43 g, 10.0 mmol) in THF (60 mL) in a 250-mL round-bottom flask under nitrogen was added CDI (1.94 g, 12.0 mmol) in portions at RT. The resulting solution was stirred for 30 min at RT. Then the reaction was stirred for 30 min at 60° C. Methanamine in THF (2 M) (40 mL, 80.0 mmol) was added dropwise at RT. The resulting solution was stirred for 16 h at RT. The reaction was then quenched by the addition of 90 mL of water. The resulting solution was extracted with 3×120 mL of DCM and the organic layers were combined and dried over anhydrous Na₂SO₄. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1).This resulted in 1.80 g (70.3%) of the title compound as yellow solid. MS-ESI: 257 (M+1).

Steps 3-4 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford intermediate 125 from compound 366″. MS-ESI: 370 (M+1).

Intermediate 126

N′-(tert-butyldimethylsilyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazole-5-sulfonimidamide Step 1: 2,2-Dimethyl-5-(thiazol-2-yl)-1,3-dioxan-5-ol

To a stirred solution of 2-bromothiazole (4.89 g, 30.0 mmol) in THF (200 mL) in a 500-mL 3-necked round-bottom flask under nitrogen was added n-BuLi/hexane (2.5 M, 12 mL, 30.0 mmol) dropwise with stirring at −78° C. The resulting solution was stirred for 30 min at −78° C. Then 2,2-dimethyl-1,3-dioxan-5-one (3.90 g, 30.0 mmol) in THF (10 mL) was added dropwise at −70° C. The resulting solution was allowed to react, with stirring, for an additional 30 min at RT. The resulting mixture was quenched with 20 mL of MeOH and concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1/10). This resulted in 3.20 g (49.6%) of the title compound as a yellow solid. MS-ESI: 216 (M+1).

Step 2: Lithium 2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazole-5-sulfinate

To a stirred solution of 2,2-dimethyl-5-(thiazol-2-yl)-1,3-dioxan-5-ol (2.15 g, 10.0 mmol) in THF (100 mL) in a 250-mL 3-necked round-bottom flask under nitrogen was n-BuLi/hexane (2.5 M, 4.0 mL, 10.0 mmol) dropwise with stirring at −70° C. The resulting solution was stirred for 60 min at −70° C. Then SO₂ (g) was bubbled to the solution at −50° C. for 10 min. The resulting solution was allowed to react, with stirring, for an additional 30 min at 20° C. The resulting mixture was concentrated under reduced pressure. This resulted in 2.5 g (crude) of the title compound as an off-white solid. MS-ESI: 278 (M−1).

Step 3: 2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazole-5-sulfonamide

To a stirred solution of lithium 2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazole-5-sulfinate (2.5 g, crude) in DCM (100 mL) in a 250-mL round-bottom flask was added NCS (2.67 g, 20.0 mmol) in small portions at RT. The resulting solution was stirred for 2 h at RT. The resulting solution was diluted with 50 mL of water, then extracted with 3×50 mL of DCM and the organic layers were combined and dried over anhydrous Na₂SO₄. Then NH₃ (g) was bubbled into reaction mixture for 10 min at 0° C. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1/3). This resulted in 1.80 g (61.2% over two steps) of the title compound as a yellow solid. MS-ESI: 293 (M−1).

Step 4-5 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford intermediate 126 from compound 371″. MS-ESI: 408 (M+1).

Intermediate 127

4-(Azetidin-1-ylmethyl)-N′-(tert-butyldimethylsilyl)-2-fluorobenzenesulfonimidamide Step 1: (4-Amino-3-fluorophenyl)(azetidin-1-yl)methanone

To a stirred solution of 4-amino-3-fluorobenzoic acid (5.0 g, 32.3 mmol) in DMF (50 mL) in a 250 mL round-bottom flask was added DIEA (8.33 g, 64.6 mmol) and HATU (24.5 g, 64.6 mmol) at 0° C. This was followed by the addition of azetidine (3.68 g, 64.6 mmol) in DMF (10 mL) dropwise with stirring at 0° C. The resulting mixture was stirred for 16 h at RT. The reaction was then quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc (5×100 mL). The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1/2) to afford the title compound (5.71 g, 91.2%) as a light yellow solid. MS-ESI: 195 (M+1).

Step 2: 4-(Azetidine-1-carbonyl)-2-fluorobenzenesulfonamide

To a stirred solution of (4-amino-3-fluorophenyl)(azetidin-1-yl)methanone (3.88 g, 20.0 mmol) in HCl (6 M, 30 mL) in a 250-mL 3-necked round-bottom flask under nitrogen was added a solution of NaNO₂ (1.66 g, 24.0 mmol) in H₂O (5 mL) dropwise with stirring at 0° C., the solution was stirred for 30 min, this solution was assigned as solution A. Then CuCl₂ (1.34 g, 10.0 mmol) was added to a 250-mL single necked round-bottom flask with AcOH (40 mL) as the solvent. Then SO₂ (g) was bubbled to the reaction mixture with stirring at RT for 20 min, this solution was assigned as solution B. To the solution B was added solution A dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at RT. The reaction mixture was diluted with 100 mL of water, extracted with 3×100 mL of DCM and the organic layers were combined and dried over anhydrous Na₂SO₄. To the crude DCM solution (-300 mL) was bubbled NH₃ (g) with stirring at 0° C. for 10 min. The resulting solution was stirred for 2 h at RT. The solution was concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:1). This resulted in 2.61 g (50.6%) of the title compound as yellow oil. MS-ESI: 257 (M−1).

Step 3: 4-(Azetidin-1-ylmethyl)-2-fluorobenzenesulfonamide

To a stirred solution of 4-(azetidine-1-carbonyl)-2-fluorobenzenesulfonamide (1.0 g, 3.88 mmol) in THF (20 mL) was added LiAlH₄ (441 mg, 11.6 mmol) in portions at 0° C. The resulting mixture was stirred for 16 h at 70° C. The reaction was quenched with 10 g of solid Na₂SO₄.10H₂O at 0° C. The resulting mixture was filtered and the filter cake was washed with EtOAc (2×50 mL). The filtrate was concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1:1) to afford the title compound (613 mg, 64.8%) as a light yellow solid. MS-ESI: 245 (M+1).

Steps 4-5 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford intermediate 127 from compound 376″. MS-ESI: 358 (M+1).

Intermediate 128

Tert-butyl 3-(3-fluoro-4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)phenyl)-pyrrolidine-1-carboxylate Step 1: Tert-butyl 3-(3-fluoro-4-sulfamoylphenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate

To a stirred solution of 4-bromo-2-fluorobenzenesulfonamide (20.0 g, 78.7 mmol) in 1,4-dioxane/H₂O (5:1) (200 mL) in a 250-mL 3-necked round-bottom flask under nitrogen was added tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H -pyrrole-1-carboxylate (27.9 g, 94.4 mmol) then K₂CO₃ (21.8 g, 157 mmol) and Pd(dppf)Cl₂ (11.5 g, 15.7 mmol) were added to the solution at RT. The resulting solution was stirred for 16 h at 90° C. The insoluble matter was filtered out and the filtrate was concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1/3) to give the title compound (7.32 g, 27.2%) as white solid. MS-ESI: 343 (M+1).

Step 2: Tert-butyl 3-(3-fluoro-4-sulfamoylphenyl)pyrrolidine-1-carboxylate

To a stirred solution of tert-butyl 3-(3-fluoro-4-sulfamoylphenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (7.30 g, 21.3 mmol) in MeOH (200 mL) in a 500 mL round-bottom flask under nitrogen was added Pd/C (10% wt. 1.0 g) in portions. The flask was evacuated and refilled three times with hydrogen. The resulting solution was stirred for 2 h at RT under atmosphere of hydrogen with a balloon. The solid was filtered out. The resulting mixture was concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1:2) to give the title compound (6.30 g, 86.0%) as white solid. MS-ESI: 345 (M+1).

Steps 3-5 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford compound 383″ from compound 380″. MS-ESI: 458 (M+1).

Step 6: Tert-Butyl 3-(4-(N-(tert-butyldimethylsilyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamidimidoyl)-3-fluorophenyl)pyrrolidine-1-carboxylate

To a stirred solution of tert-butyl 3-(4-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)-3-fluorophenyl)-pyrrolidine-1-carboxylate (5.2 g, 11.3 mmol) in THF (100 mL) in a 100-mL 3-necked round-bottom purged with and maintained under nitrogen was added NaH (60% dispersion in mineral oil, 820 mg, 34 mmol) in portions at 0° C. The reaction mixture was stirred for 15 min at RT. 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (2.7 g, 13.6 mmol) in THF (10 mL) was added dropwise to the solution at 0° C. The resulting solution was stirred for 60 min at RT. The resulting mixture was quenched with 5 mL of water, then concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1:6) to give title compound (5.1 g, 69%) as white solid. MS-ESI: 657 (M+1).

Step 7: Tert-Butyl 3-(3-fluoro-4-(N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamidimidoyl)phenyl)pyrrolidine-1-carboxylate

To a stirred solution of tert-butyl 3-(4-(N-(tert-butyldimethylsilyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)-3-fluorophenyl)pyrrolidine-1-carboxylate (5.1 g, 7.8 mmol) in DCM (100 mL) in a 500 mL round-bottom flask was added TFA (5 mL) dropwise at 0° C. The resulting solution was stirred for 60 min at RT. The resulting mixture was concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1:8) to give the title compound (1.2 g, 35%) as white solid. MS-ESI: 543 (M+1).

Intermediate 128A and 128B

Intermediate 128A and 128B (Stereochemistry Not Assigned) (R)- and (S)-Tert-butyl 3-(3-fluoro-4-(N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)-phenyl)pyrrolidine-1-carboxylate Step 8: Tert-butyl 3-(3-fluoro-4-((R)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulamidimidoyl)-phenyl)pyrrolidine-1-carboxylate and tert-butyl 3-(3-fluoro-4-((S)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)phenyl)pyrrolidine-1-carboxylate

Tert-Butyl 3-(3-fluoro-4-(N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)phenyl) pyrrolidine-1-carboxylate (1.2 g) was resolved by Prep chiral SFC with the following conditions: Column: (R,R)Whelk, 21.1*250 mm, 5 um; Mobile Phase A: CO₂, Mobile Phase B: MeOH; Flow rate: 40 mL/min; Gradient: 40% B; 220 nm; Rt₁: 7.14 min (Intermediate 128A, 480 mg, 98%de); Rt₂: 10.3 min (Intermediate 128B, 500 mg, 98% de) both as an off white solid. MS-ESI: 543 (M+1).

Intermediate 129

Tert-butyl 2-(4-(N-(tert-butyldimethylsilyl)sulfamidimidoyl)phenyl)azetidine-1-carboxylate Step Tert-butyl (1-(4-bromophenyl)-3-hydroxypropyl)carbamate

To a stirred solution of 3-amino-3-(4-bromophenyl)propan-1-ol (6.90 g, 30.0 mmol) in THF (100 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% dispersion in mineral oil, 1.80 g, 45.0 mmol) in portions at 0° C. The resulting solution was stirred for 20 min at RT. This was followed by the addition of (Boc)₂O (9.81 g, 45.0 mmol) in THF (10 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 16 h at RT. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3×100 mL of EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:4). This resulted in 8.43 g (85.2%) of the title compound as a yellow solid. MS-ESI: 330/332 (M+1).

Step 2: Tert-butyl (1-(4-bromophenyl)-3-((tert-butyldimethylsilyl)oxy)propyl)carbamate

To a stirred solution of tert-butyl (1-(4-bromophenyl)-3-hydroxypropyl)carbamate (6.60 g, 20.0 mmol) in THF (100 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% dispersion in mineral oil, 1.20 g, 30.0 mmol) in portions at 0° C. The resulting solution was stirred for 20 min at RT. This was followed by the addition of TBSCl (4.53 g, 30.0 mmol) in THF (10 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3×100 mL EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:5). This resulted in 7.81 g (87.9%) of the title compound as a yellow solid. MS-ESI: 444/446 (M+1).

Steps 3-4 used similar procedures for converting compound 369″ to compound 371″ shown in Scheme 82 to afford compound 389″ from compound 387″. MS-ESI: 445 (M+1).

Step 5: Tert-butyl (3-hydroxy-1-(4-sulfamoylphenyl)propyl)carbamate

To a stirred solution of tert-butyl (3-((tert-butyldimethylsilyl)oxy)-1-(4-sulfamoylphenyl)propyl)carbamate (1.50 g, 3.37 mmol) in THF (30 mL) in a 100-mL round-bottom flask was added TBAF (1.76 g, 6.74 mmol) in several batches at RT. The resulting solution was stirred for 30 min at RT. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3×150 mL of EtOAc and the organic layers were combined and dried over Na₂SO₄ and concentrated under reduced pressure. The residue was eluted from silica gel with DCM/MeOH (20/1). This resulted in 896 mg (80.6%) of the title compound as a yellow solid. MS-ESI: 331 (M+1).

Step 6: 3-((Tert-butoxycarbonyl)amino)-3-(4-sulfamoylphenyl)propyl methanesulfonate

To a stirred solution of tert-butyl (3-hydroxy-1-(4-sulfamoylphenyl)propyl) carbamate (660 mg, 2.00 mmol) in DCM (20 mL) in a 100-mL round-bottom flask under nitrogen was added TEA (404 mg, 4.00 mmol) at RT, then methanesulfonyl chloride (230 mg, 2.00 mmol) dropwise at 0° C. The resulting solution was stirred for 4 h at 0° C. The reaction was then quenched by the addition of 10 mL of water/ice. The resulting solution was extracted with 3×150 mL of EtOAc and the organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated. To the residue was added 10 mL of EtOAc/PE (1:5) and the turbid solution was sonicated for 5 min. The product was collected by filtration. This resulted in 635 mg (77.8%) of the title compound as a white solid. MS-ESI: 409 (M+1).

Step 7: 3-amino-3-(4-sulfamoylphenyl)propyl methanesulfonate

To a stirred solution of 3-((tert-butoxycarbonyl)amino)-3-(4-sulfamoylphenyl)propyl methanesulfonate (635 mg, 1.56 mmol) in DCM (15 ml) in a 100-mL round-bottom flask was added TFA (5 ml) dropwise at RT. The resulting solution was stirred for 16 h at RT. The resulting mixture was concentrated under vacuum. The crude product was used in the next step directly without further purification. This resulted in 500 mg (crude) of the title compound as yellow oil. MS-ESI: 309 (M+1).

Step 8: 4-(Azetidin-2-yl)benzenesulfonamide

To a stirred solution of 3-amino-3-(4-sulfamoylphenyl)propyl methanesulfonate (500 mg, crude) in 2-methyl-2-propanol (20 mL) in a 100-mL round-bottom flask. The pH value of the solution was adjusted to 12 with NaOH (4 M). The resulting solution was stirred for 4 h at 60° C. The resulting solution was extracted with 3×50 mL of EtOAc and the organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated. The product was used in the next step directly without further purification. This resulted in 800 mg (crude) of the title compound as yellow oil. MS-ESI: 213 (M+1).

Step 9: Tert-butyl 2-(4-sulfamoylphenyl)azetidine-1-carboxylate

To a stirred solution of 4-(azetidin-2-yl)benzenesulfonamide (800 mg, crude) in THF (10 mL) in a 50-mL round-bottom flask was added TEA (253 mg, 2.50 mmol), this was followed by the addition of (Boc)₂O (545 mg, 2.50 mmol) in THF (5 mL) dropwise at RT. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×30 mL of EtOAc and the organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 200 mg (41% over three steps) of the title compound as a yellow solid. MS-ESI: 313 (M+1).

Steps 10-11 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford intermediate 129 from compound 394″. MS-ESI: 426 (M+1).

Intermediate 130

1-(4-(N′-(Tert-butyldimethylsilyl)sulfamidimidoyl)-3-fluorophenyl)-N-methylcyclopropane-1-carboxamide Step 1: Methyl 2-(4-bromo-3-fluorophenyl)acetate

To a stirred solution of 2-(4-bromo-3-fluorophenyl)acetic acid (10.0 g, 42.9 mmol) in MeOH (200 mL) in a 500-mL round-bottom flask under nitrogen was added SOCl₂ (10.2 g, 85.8 mmol) dropwise at 0° C. over 30 min. The resulting solution was stirred for 16 h at RT. The resulting solution was concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:1). This resulted in 10.0 g (94.3%) of the title compound as an orange solid. MS-ESI: 247/249 (M+1).

Step 2: Methyl 1-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxylate

To a stirred solution of methyl 2-(4-bromo-3-fluorophenyl)acetate (10.0 g, 40.5 mmol) in DMF (200 mL) in a 500-mL round-bottom flask under nitrogen. This was followed by the addition of NaH (60% dispersion in mineral oil, 4.88 g, 122 mmol) in portions at 0° C. To this was added 1,2-dibromoethane (11.4 g, 60.7 mmol) dropwise at 0° C. The resulting solution was stirred for 3 days at RT. The reaction was then quenched with 50 mL of water. The resulting solution was extracted with EtOAc (3×100 mL). The organic layers were combined and washed with brine (300 mL), then dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:1). This resulted in 5.0 g (45.2%) of the title compound as a yellow solid.

Steps 3-4 used similar procedures for converting compound 364″ to compound 366″ shown in Scheme 81 to afford compound 400″ from compound 398″. MS-ESI: 272/274 (M+1).

Steps 5-9 used similar procedures for converting compound 369″ to intermediate 126 shown in Scheme 82 to afford intermediate 130 from compound 400″. MS-ESI: 386 (M+1).

Intermediate 131

N′-(tert-butyldimethylsilyl)-6-(2-hydroxypropan-2-yl)pyridine-3-sulfonimidamide

Step 1 used similar procedures for converting compound 374″ to compound 375″ shown in Scheme 83 to afford compound 406″ from compound 405″. MS-ESI: 217 (M+1).

Step 2: 6-(2-Hydroxypropan-2-yl)pyridine-3-sulfonamide

To a stirred solution of methyl 5-sulfamoylpicolinate (4.80 g, 22.2 mmol) in THF (300 mL) in a 500-mL 3-necked round-bottom flask under nitrogen was added MeMgBr/THF (3 M, 74 mL, 222 mmol) dropwise at 0° C. The resulting solution was stirred for 16 h at RT. The reaction was then quenched with 50 mL of NH₄Cl (aq). The resulting solution was extracted with 3×100 ml of EtOAc and the organic layers were combined and dried over Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (60:1). This resulted in 2.46 g (51.3%) of the title compound as a light yellow solid. MS-ESI: 215 (M−1).

Steps 3-4 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford intermediate 131 from compound 407″. MS-ESI: 330 (M+1).

TABLE 30 The Intermediate 132 was prepared using similar procedures for converting compound 405″ to Intermediate 131 shown in Scheme 87 from appropriate starting materials. Intermediate Exact Mass # Structure IUPAC Name [M + H]⁺ Intermediate 132

N′-(tert-butyldimethylsilyl)- 4-(2-hydroxypropan-2- yl)pyridine-2-sulfonimidamide 330

Intermediate 133

N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-(4-methoxybenzyl)-1H-pyrazole-3-sulfonimidamide Step 1: Methyl 1-(4-methoxybenzyl)-3-nitro-1H-pyrazole-5-carboxylate

To a stirred solution of methyl 3-nitro-1H-pyrazole-5-carboxylate (8.0 g, 46.8 mmol) in DMF (70 mL) in a 250 mL round-bottom flask was added TEA (26.8 g, 187 mmol) and 4-methoxybenzyl chloride (14.64 g, 93.5 mmol) dropwise at RT, the solution was stirred for 16 h at RT. The resulting mixture was quenched with 100 mL of water and extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This resulted in a mixture of the title compound and methyl 1-(4-methoxybenzyl)-5-nitro-1H-pyrazole-3-carboxylate (˜6:1) (11.3 g, 82.9%) as a light yellow oil. MS-ESI: 292 (M+1).

Step 2: Methyl 3-amino-1-(4-methoxybenzyl)-1H-pyrazole-5-carboxylate

To a stirred solution of the mixture methyl 2-[(4-methoxyphenyl)methyl]-5-nitropyrazole-3-carboxylate and methyl 1-(4-methoxybenzyl)-5-nitro-1H-pyrazole-3-carboxylate (11.3 g, 38.8 mmol) in MeOH (500 mL) in a 1000 mL round-bottom flask under nitrogen was added Pt/C (5% wt., 1.50 g) in portions. The flask was evacuated and flushed 3 times with hydrogen. The solution was stirred for 16 h at RT under hydrogen atmosphere with a balloon. The resulting mixture was filtered, the filter cake was washed with MeOH (3×50 mL). The filtrate was concentrated under reduced pressure. The crude product was eluted from silica gel with EtOAc/PE (1:3). This resulted in the title compound (7.1 g, 70.1%) as a light yellow solid. MS-ESI: 262 (M+1).

Steps 3-7 used similar procedures for converting compound 405″ to Intermediate 131 shown in Scheme 87 to afford Intermediate 133 from compound 411″. MS-ESI: 439 (M+1).

Intermediate 134

N′-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)-4-(methoxymethyl)thiazole-5-sulfonimidamide Step 1: (2-Bromothiazol-4-yl) MeOH

To a stirred solution of methyl 2-bromothiazole-4-carboxylate (10.0 g, 45.0 mmol) in EtOH (150 mL) in a 250-mL round-bottom flask was added NaBH₄ (3.42 g, 90.0 mmol) in portions at RT. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of 200 mL of water. The resulting solution was extracted with 3×300 ml of EtOAc and concentrated. The crude product was eluted from silica gel with EtOAc/PE (1:5). This resulted in 8.0 g (91.6%) of the title compound as yellow oil. MS-ESI: 196/194 (M+1).

Step 2: 2-Bromo-4-(methoxymethyl)thiazole

To a stirred solution of (2-bromothiazol-4-yl)methanol (8.0 g, 41.2 mmol) in THF (100 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% dispersion in mineral oil, 1.65 g, 82.4 mmol) in portions at 0° C. The resulting solution was stirred for 20 min at RT. This was followed by the addition of CH₃I (6.43 g, 45.3 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 16 h at RT. The reaction was then quenched with 200 mL of water. The resulting solution was extracted with 3×200 ml of EtOAc and the organic layers combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:30). This resulted in 7.0 g (81.7%) of the title compound as a light yellow solid. MS-ESI: 210/208 (M+1).

Step 3: 2-(4-(Methoxymethyl)thiazol-2-yl)propan-2-ol

To a stirred solution of 2-bromo-4-(methoxymethyl)thiazole (7.0 g, 33.6 mmol) in THF (70 mL) a 250-mL 3-necked round-bottom flask under nitrogen was added n-BuLi/hexane (2.5 M, 14.8 mL, 37.0 mmol) dropwise at −78° C. over 30 min. To this was added acetone (2.15 g, 37.0 mmol) dropwise with stirring at −78° C. The resulting solution was stirred for 50 min at RT. The reaction was then quenched by the addition of 80 mL of water/ice. The resulting solution was extracted with 3×80 mL of EtOAc. The resulting mixture was washed with 2 ×50 mL of water. The mixture was dried over anhydrous Na₂SO₄. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1/5). This resulted in 3.20 g (50.8%) of the title compound as yellow oil. MS-ESI: 250 (M−1).

Steps 4-7 used similar procedures for converting compound 369″ to intermediate 126 shown in Scheme 82 to afford intermediate 134 from compound 419″. MS-ESI: 380 (M+1).

Intermediate 135

N′-(tert-butyldimethylsilyl)-4-(1-(dimethylamino)-2,2-difluoroethyl)benzenesulfonimidamide Step 1: 1-(4-Bromophenyl)-2,2-difluoroethan-1-one

To a stirred solution of 1,4-dibromobenzene (10.0 g, 42.4 mmol) in THF (300 mL) a 500-mL 3-necked round-bottom flask under nitrogen was added n-BuLi/hexane (2.5 M, 18.6 mL, 46.6 mmol) dropwise at −70° C. The resulting solution was stirred for 30 min at −70° C. Then to this was added ethyl ethyl 2,2-difluoroacetate (15.7 g, 127 mmol) in THF (20 mL) dropwise at −70° C. The resulting solution was stirred for 30 min at −70° C. The reaction was then quenched by the addition of 200 mL of water. The resulting solution was extracted with 3×200 mL of DCM and the combined organic layers dried over Na₂SO₄, then concentrated under reduced pressure. This resulted in 6.0 g (crude) of the title compound as a yellow oil. MS-ESI: 235/237 (M+1).

Step 2: 1-(4-Bromophenyl)-2,2-difluoroethan-1-ol

To a stirred solution of 1-(4-bromophenyl)-2,2-difluoroethan-1-one (6.0 g, crude) in ethanol (40 mL) in a 50-mL round-bottom flask under nitrogen was added NaBH₄ (3.22 g, 84.8 mmol) in portions at 0° C. The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3×20 mL of DCM, the combined organic layers were dried over Na₂SO₄ and then concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1/5). This resulted in 5 g (49.8% over two steps) of the title compound as brown oil. MS-ESI: 237/239 (M+1).

Step 3: 1-(4-Bromophenyl)-2,2-difluoroethyl methanesulfonate

To a stirred solution of 1-(4-bromophenyl)-2,2-difluoroethan-1-ol (4.74 g, 20.0 mmol) in DCM (100 mL) in a 250-mL round-bottom flask was added TEA (6.06 g, 60.0 mmol) at RT. This was followed by the addition of methanesulfonyl chloride (3.45 g, 30.0 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 30 min at RT. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3×100 mL of DCM, the combined organic layers were dried over Na₂SO₄ and then concentrated under vacuum. This resulted in 5.53 g (87.7%) of the title compound as brown oil. MS-ESI: 315/317 (M+1).

Step 4: 1-(4-Bromophenyl)-2,2-difluoro-N,N-dimethylethan-1-amine

To a stirred solution of 1-(4-bromophenyl)-2,2-difluoroethyl methanesulfonate (5.53 g, 17.6 mmol) in THF (100 mL) in a 250-mL round-bottom flask was added dimethylamine in THF (2 M, 352 mL, 704 mmol) dropwise at 0° C. The resulting solution was stirred for 14 h at 60° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 3.96 g (85.2%) of the title compound as brown oil. MS-ESI: 264/266 (M+1).

Steps 5-8 used similar procedures for converting compound 369″ to Intermediate 126 shown in Scheme 82 to afford Intermediate 135 from compound 427″. MS-ESI: 378 (M+1).

Intermediate 136

N′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-phenylthiophene-2-sulfonimidamide Step 1: Methyl 2-bromo-5-(chlorosulfonyl)thiophene-3-carboxylate

To a stirred solution of methyl 2-bromothiophene-3-carboxylate (4.42 g, 20.0 mmol) in CHCl₃ (100 mL) in a 250-mL round-bottom flask was added HSO₃Cl (7.02 g, 60.0 mmol) dropwise at 0° C. The resulting solution was stirred for 16 h at RT. This was followed by the addition of PCl₅ (12.5 g, 60.0 mmol) in several batches at 0° C. The resulting solution was stirred for 3 h at 60° C. in an oil bath. The reaction mixture was poured into 200 mL of water/ice slowly. The resulting solution was extracted with 3×100 mL of DCM, the combined organic layers dried over Na₂SO₄ then concentrated under vacuum. This resulted in 4.50 g (crude) of the title compound as light yellow oil.

Step 2: Methyl 2-bromo-5-sulfamoylthiophene-3-carboxylate

To a stirred solution of methyl 2-bromo-5-(chlorosulfonyl)thiophene-3-carboxylate (4.50 g, crude) in DCM (100 mL) in a 250-mL round-bottom flask. Then NH₃ (g) was introduced to the reaction mixture with stirring at 0° C. for 10 min. The resulting solution was stirred for 2 h at 25° C., the mixture was concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:1). This resulted in 3.04 g (50.6%) of the title compound as yellow solid. MS-ESI: 300/298 (M−1).

Step 3: Methyl 2-phenyl-5-sulfamoylthiophene-3-carboxylate

To a stirred solution of methyl 2-bromo-5-sulfamoylthiophene-3-carboxylate (3.0 g, 10.0 mmol) in dioxane (100 mL)/H₂O (10 mL) in a 500-mL 3-necked round-bottom flask under nitrogen was added Cs₂CO₃ (8.15 g, 25.0 mmol). Then phenylboronic acid (3.05 g, 25.0 mmol), Xphos (477 mg, 1.0 mmol) and Pd(dppf)Cl₂ (732 mg, 1.0 mmol) were added at RT. The resulting solution was stirred for 16 h at 80° C. in an oil bath. The insoluble was filtered out and the filtrate was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 1.81 g (61.1%) of the title compound as yellow oil. MS-ESI: 296 (M−1).

Steps 4-7 used similar procedures for converting compound 406″ to intermediate 131 shown in Scheme 87 to afford intermediate 136 from compound 434″. MS-ESI: 411 (M+1).

Intermediate 137

N′-(tert-butyldimethylsilyl)-4-(1-(dimethylamino)-2-fluoroethyl)benzenesulfonimidamide Step 1: 2-Amino-2-(4-bromophenyl)ethan-1-ol

To a stirred solution of 2-amino-2-(4-bromophenyl)acetic acid (5.0 g, 21.7 mmol) in THF (200 mL) in a 500-mL 3-necked round-bottom flask under nitrogen was added BH₃/THF (1M, 108 mmol, 108 mL) dropwise at 0° C. in an ice bath. The resulting solution was stirred for 16 h at 50° C. in an oil bath. The reaction was then quenched by the addition of 50 mL of MeOH. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 2.67 g (56.9%) of the title compound as yellow oil. MS-ESI: 216/218 (M+1).

Step 2: 2-(4-Bromophenyl)-2-(dimethylamino)ethan-1-ol

To a stirred solution of 2-amino-2-(4-bromophenyl)ethan-1-ol (2.67 g, 12.4 mmol) in HCOOH (10 mL) in a 100-mL round-bottom flask under nitrogen was added (HCHO)_(n) (1.12 g, 37.2 mmol) at 0° C. The resulting solution was stirred for 2 h at 85° C. in an oil bath. The pH value of the solution was adjusted to 10 with Na₂CO₃ (5 M). The resulting solution was extracted with 3×100 mL of EtOAc, the combine organic layers was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 2.37 g (78.3%) of the title compound as a yellow solid. MS-ESI: 244/246 (M+1).

Step 3: 1-(4-Bromophenyl)-2-fluoro-N,N-dimethylethan-1-amine

To a stirred solution of 2-(4-bromophenyl)-2-(dimethylamino)ethan-1-ol (1.22 g, 5.00 mmol) in DCM (20 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added DAST (4.03 g, 25.0 mmol) dropwise at 0° C. The resulting solution was stirred for 16 h at RT. The reaction was then quenched by the addition of 10 mL of water/ice. The pH value of the solution was adjusted to 9 with NaHCO₃ (6 M). Then the mixture was extracted with EtOAc (3×50 mL) and the organic layers were combined and dried over anhydrous Na₂SO₄, then concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 925 mg (75.2%) of the title compound as brown oil. MS-ESI: 246/248 (M+1).

Step 4: Lithium 4-(1-(dimethylamino)-2-fluoroethyl)benzenesulfinate

To a stirred solution of 1-(4-bromophenyl)-2-fluoro-N,N-dimethylethan-1-amine (738 mg, 3.00 mmol) in THF (30 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added n-BuLi/hexane (2.5 M, 2.40 mL, 6.0 mmol) dropwise at −78° C. The resulting solution was stirred for 30 min at −78° C. Then SO₂ (g) was bubbled into the reaction solution for 15 min below 0° C. The resulting solution was allowed to react, with stirring, for an additional 1 h at RT. The reaction was concentrated under vacuum and for next step without purification. MS-ESI: 232 (M+1).

Step 5: 4-(1-(Dimethylamino)-2-fluoroethyl)benzenesulfonamide

To a stirred solution of Lithium 4-(1-(dimethylamino)-2-fluoroethyl)benzenesulfinate (693 mg, crude) in DCM (40 mL) in a 100-mL round-bottom flask was added DCDMH (1.18 g, 6.00 mmol) at RT. Then the reaction solution was stirred for 2 h at RT. Then NH₃ (g) was bubbled into the solution for 10 min at 0° C. The resulting solution was allowed to react, with stirring, for an additional 1 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (1:10). This resulted in 163 mg (22.1% over two steps) of the title compound as yellow oil. MS-ESI: 247 (M+1).

Steps 6-8 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford intermediate 137 from compound 443″. MS-ESI: 360 (M+1).

Intermediate 138

N′-(tert-butyldimethylsilyl)-5-fluoro-2-isopropylpyridine-4-sulfonimidamide

Steps 1-3 used similar procedures for converting compound 369″ to compound 371″ shown in Scheme 82 to afford compound 449″ from compound 446″. MS-ESI: 211/213 (M+1).

Step 4: 5-Fluoro-2-(prop-1-en-2-yl)pyridine-4-sulfonamide

To a stirred solution of 2-chloro-5-fluoropyridine-4-sulfonamide (1.27 g, 6.00 mmol) in H₂O (15 mL) and dioxane (60 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (3.02 g, 18.0 mmol). Then Cs₂CO₃ (3.91 g, 12.0 mmol) and Pd(dppf)Cl₂ (439 mg, 0.600 mmol) were added. The resulting solution was stirred for 12 h at 80° C. in an oil bath. The resulted mixture was concentrated under vacuum. The resulting solution was diluted with 50 mL of H₂O. The resulting solution was extracted with 3×100 mL of DCM, the combined organic layers was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:9). This resulted in 1.18 g (90.8%) of the title compound as a dark yellow solid. MS-ESI: 217 (M+1).

Step 5: 5-Fluoro-2-isopropylpyridine-4-sulfonamide

To a stirred solution of 5-fluoro-2-(prop-1-en-2-yl)pyridine-4-sulfonamide (1.18 g, 5.46 mmol) in isopropyl alcohol (50 mL) in a 100-mL round-bottom flask under nitrogen was added Pd/C (10% wt., 200 mg), the flask was evacuated and flushed with hydrogen 3 times. The resulting solution was stirred for 3 h at RT under hydrogen with a balloon. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:9). This resulted in 1.07 g (89.9%) of the title compound as yellow oil. MS-ESI: 219 (M+1).

Steps 6-8 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford intermediate 138 from compound 451″. MS-ESI: 332 (M+1).

Intermediate 139

N′-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-4-sulfonimidamide Step 1: 2-(4-(Benzylthio) thiazol-2-yl)propan-2-ol

To a stirred solution of 2-(4-bromothiazol-2-yl)propan-2-ol (8.0 g, 36.0 mmol) in 1,2-dimethoxyethane (100 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added Na₂CO₃ (11.4 g, 108 mmol). Then phenylmethanethiol (22.3 g, 180 mmol) and XPhos Pd G2 (3.20 g, 3.60 mmol) were added. The resulting solution was stirred for 16 h at 80° C. in an oil bath. The insoluble was filtered out and the filtrate was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/hexane (1:5). This resulted in 4.99 g (52.3%) of the title compound as a yellow solid. MS-ESI: 266 (M+1).

Step 2: 2-(2-Hydroxypropan-2-yl) thiazole-4-sulfonyl chloride

To a stirred solution of 2-(4-(benzylthio) thiazol-2-yl)propan-2-ol (500 mg, 1.89 mmol) in MeCN (40 mL), H₂O (2 mL), AcOH (0.75 mL) in a 100-mL round-bottom flask was added DCDMH (1.12 g, 5.67 mmol) in MeCN (10 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at RT. The resulting mixture was diluted with 30 mL of water. The resulting solution was extracted with 3×30 mL of EtOAc, the combined organic layers was dried over anhydrous Na₂SO₄ and concentrated under vacuum. This resulted in 400 mg (crude) of the title compound as a yellow solid.

Step 3: 2-(2-Hydroxypropan-2-yl) thiazole-4-sulfonamide

To a stirred solution of 2-(2-hydroxypropan-2-yl) thiazole-4-sulfonyl chloride (400 mg, crude) in DCM (30 mL) in a 100-mL round-bottom flask bubbled NH₃ (g) at 0° C. for 10 min. The resulting solution was stirred for 20 min at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 150 mg (35.7% for Steps 2&3) of the title compound as a yellow solid. MS-ESI: 221 (M−1).

Steps 4-5 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford intermediate 139 from compound 457″. MS-ESI: 336 (M+1).

Intermediate 140

N-(tert-butyldimethylsilyl)-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-sulfonimidamide Step 6-Methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine

To a stirred solution of 4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride (1.76 g, 10.0 mmol) in THF (100 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% dispersion in mineral oil, 800 mg, 20.0 mmol) in portions at 0° C. The resulting solution was stirred for 20 min at RT. This was followed by the addition of CH₃I (4.26 g, 30.0 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 16 h at RT. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with 3×100 ml of EtOAc and the organic layers combined and dried over Na₂SO₄, then concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (18:1). This resulted in 1.25 g (81.7%) of the title compound as a light yellow solid. MS-ESI: 154 (M+1).

Steps 2-6 used similar procedures for converting compound 369″ to intermediate 126 shown in Scheme 82 to afford intermediate 140 from compound 460″. MS-ESI: 346 (M+1).

Intermediate 141

N′-(tert-butyldimethylsilyl)-4-(difluoromethoxy)benzenesulfonimidamide Step 1: 4-(Difluoromethoxy)benzenesulfonamide

To a stirred solution of 4-(difluoromethoxy)benzenesulfonyl chloride (2.43 g, 10.0 mmol) in THF (100 mL) in a 250-mL round-bottom flask was bubbled NH₃ (g) for 10 min with stirring at 0° C. The resulting solution was stirred for 2 h at RT and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:1). This resulted in 1.93 g (86.5%) of the title compound as yellow oil. MS-ESI: 222 (M−1).

Steps 2-4 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford intermediate 141 from compound 466″. MS-ESI: 337 (M+1).

Intermediate 142

Tert-butyl ((5-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)-4-fluorothiophen-2-yl)methyl)(methyl)carbamate Step 1: (4-Fluorothiophen-2-yl)methanol

To a stirred solution of methyl 4-fluorothiophene-2-carboxylate (10.0 g, 62.5 mmol) in THF (200 mL) in a 500-mL round-bottom flask under nitrogen was added LiAlH₄ (4.75 g, 125 mmol) in portions at 0° C. The resulting solution was stirred for 16 h at RT. The reaction was then quenched with 100 mL of water/ice. The insoluble was filtered out and the filtrate was extracted with EtOAc (3×200 mL). The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:1). This resulted in 7.0 g (84.8%) of the title compound as a yellow solid. MS-ESI: 133 (M+1).

Step 2-(Bromomethyl)-4-fluorothiophene

To a stirred solution of (4-fluorothiophen-2-yl)methanol (7.0 g, 53.0 mmol) in DCM (150 mL) in a 500-mL round-bottom flask was added PBr₃ (17.2 g, 63.6 mmol) dropwise at 0° C. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of 60 mL of water. The resulting solution was extracted with DCM (3×50 mL). The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:5). This resulted in 8.0 g (77.4%) of the title compound as a yellow solid.

Step 3: 1-(4-Fluorothiophen-2-yl)-N-methylmethanamine

To a stirred solution of 2-(bromomethyl)-4-fluorothiophene (8.00 g, 41.0 mmol) in THF (100 mL) in a 250-mL round-bottom flask was added methanamine in THF (2 M, 41 mL, 82.0 mmol) at RT. The resulting solution was stirred for 16 h at RT. The reaction was then quenched with 50 mL of water. The resulting solution was extracted with EtOAc (3×100 mL). The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:1). This resulted in 4.0 g (67.3%) of the title compound as a yellow solid. MS-ESI: 146 (M+1).

Step 4: Tert-butyl ((4-fluorothiophen-2-yl)methyl)(methyl)carbamate

To a stirred solution of 1-(4-fluorothiophen-2-yl)-N-methylmethanamine (4.0 g, 27.6 mmol) in THF (40 mL) in a 100-mL round-bottom flask under nitrogen was added NaH (60% dispersion in mineral oil, 1.66 g, 41.4 mmol) in portions at 0° C. The resulting solution was stirred for 20 min at RT. This was followed by the addition of (Boc)₂O (9.03 g, 41.4 mmol) in THF (5 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 16 h at RT. The reaction was then quenched with 10 mL of water. The resulting solution was extracted with EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:3). This resulted in 5.0 g (74.0%) of the title compound as a yellow solid. MS-ESI: 246 (M+1).

Steps 5-8 used similar procedures for converting compound 369″ to intermediate 126 shown in Scheme 82 to afford intermediate 142 from compound 470″. MS-ESI: 438 (M+1).

Intermediate 143

Tert-butyl 2-(4-(N-(tert-butyldimethylsilyl)sulfamidimidoyl)phenyl)pyrrolidine-1-carboxylate Step 1: 2,2,2-Trifluoro-1-(2-phenylpyrrolidin-1-yl)ethan-1-one

To a stirred solution of 2-phenylpyrrolidine (16.5 g, 112 mmol) in DCM (200 mL) in a 500-mL round-bottom flask under nitrogen was added TEA (22.6 g, 224 mmol) followed by TFAA (16.0 mL) dropwise at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched with 100 mL of water. The resulting solution was extracted with 3×200 mL of DCM. The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:4). This resulted in 20.0 g (73.5%) of the title compound as yellow oil. MS-ESI: 244 (M+1).

Step 2: 4-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzenesulfonyl chloride

To a stirred solution of 2,2,2-trifluoro-1-(2-phenylpyrrolidin-1-yl)ethan-1-one (4.86 g, 20.0 mmol) in CHCl₃ (100 mL) in a 250-mL round-bottom flask was added HSO₃Cl (7.02 g, 60.0 mmol) dropwise at 0° C. The resulting solution was stirred for 16 h at RT. This was followed by the addition of PCl₅ (12.5 g, 60.0 mmol) in several batches at 0° C. The resulting solution was stirred for 3 h at 60° C. in an oil bath. The reaction mixture was poured into 200 mL of water/ice slowly. The resulting solution was extracted with 3×100 mL of DCM. The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. This resulted in 5.10 g (crude) of the title compound as light yellow oil.

Step 3: 4-(1-(2,2,2-Trifluoroacetyl)pyrrolidin-2-yl)benzenesulfonamide

To a stirred solution of 4-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzenesulfonyl chloride (5.10 g, crude) in DCM (100 mL) in a 250-mL round-bottom flask. Then NH₃ (g) was introduced into the reaction solution with stirring at 0° C. for 10 min. The resulting solution was stirred for 2 h at RT and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:1). This resulted in 3.26 g (50.6%, over two steps) of the title compound as a yellow solid. MS-ESI: 321 (M−1).

Step 4: 4-(Pyrrolidin-2-yl)benzenesulfonamide

To a stirred solution of 4-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzenesulfonamide (3.22 g, 10.0 mmol) in MeOH (30 mL) in a 250-mL round-bottom flask under nitrogen was added K₂CO₃ (4.14 g, 30.0 mmol). The resulting solution was stirred for 16 h at RT. The solids were filtered out and the filter cake was washed with 3×100 mL of EtOAc, the filtrate and the wash were combined and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:1). This resulted in 1.86 g (82.1%) of the title compound as yellow oil. MS-ESI: 227 (M+1).

Step 5: Tert-butyl 2-(4-sulfamoylphenyl)pyrrolidine-1-carboxylate

To a stirred solution of 4-(pyrrolidin-2-yl)benzenesulfonamide (1.13 g, 5.0 mmol) in DCM (30 mL) in a 250-mL round-bottom flask under nitrogen was added NaHCO₃ (840 mg, 10.0 mmol) and Boc₂O (1.20 g, 5.50 mmol) in portions at RT. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3×50 mL of DCM and the organic layers combined and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:1). This resulted in 1.24 g (76.3%) of the title compound as yellow oil. MS-ESI: 327 (M+1).

Steps 6-7 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford intermediate 143 from compound 479″. MS-ESI: 440 (M+1).

Intermediate 144

N′-(tert-butyldimethylsilyl)-6-cyclopentylpyridine-3-sulfonimidamide

Steps 1-2 used similar procedures for converting compound 374″ to compound 375″ shown in Scheme 83 to afford compound 219 from compound 217. MS-ESI: 239/237 (M+1).

Step 3: 6-Cyclopentylpyridine-3-sulfonamide

To a stirred solution of 6-bromopyridine-3-sulfonamide (2.00 g, 8.44 mmol) in THF (20 mL) in a 250-mL round-bottom flask under nitrogen were added Pd(dppf)Cl₂ (309 mg, 0.422 mmol). Then CuI (161 mg, 0.844 mmol) was added and cyclopentylzinc(II) bromide (1M in THF, 34.0 mL) dropwise at RT under nitrogen. The resulting mixture was stirred overnight at 80° C. under nitrogen. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE (1:2) to afford the title compound (1.70 g, 89.2%) as a yellow solid. MS-ESI: 225 (M−1).

Steps 4-5 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford intermediate 144 from compound 481″. MS-ESI: 340 (M+1).

Intermediate 145

Tert-butyl (2-(4-(N′-(tert-butyldiphenylsilyl)sulfamidimidoyl)-3-fluorophenyl)propan-2-yl)(methyl)carbamate Step 1: 2-Fluoro-4-(prop-1-en-2-yl)benzenesulfonamide

To a stirred solution of 4-bromo-2-fluorobenzenesulfonamide (10.2 g, 40.0 mmol) in dioxane (300 mL) and H₂O (30 mL) in a 500-mL round-bottom flask under nitrogen was added Cs₂CO₃ (32.6 g, 100 mmol). Then 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (16.8 g, 100 mmol) and Pd(dppf)Cl₂ (1.46 g, 2.00 mmol) were added. The resulting solution was stirred for 16 h at 90° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 6.09 g (70.8%) of the title compound as yellow oil. MS-ESI: 216 (M+1).

Step 2: 2-Chloro-N-(2-(3-fluoro-4-sulfamoylphenyl)propan-2-yl)acetamide

To a stirred solution of 2-fluoro-4-(prop-1-en-2-yl)benzenesulfonamide (6.02 g, 28.0 mmol) in AcOH (150 mL) in a 500-mL round-bottom flask under nitrogen was added 2-chloroacetonitrile (21.0 g, 280 mmol), then H₂SO₄ (30 mL) was added dropwise at 0° C. The resulting solution was stirred for 12 h at RT. The resulting solution was poured into 200 mL of water/ice. The pH value of the solution was adjusted to 7 with NaOH (6 M). The resulting solution was extracted with 3×300 mL of EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 4.42 g (51.1%) of the title compound as a yellow solid. MS-ESI: 309 (M+1).

Step 3: 4-(2-Aminopropan-2-yl)-2-fluorobenzenesulfonamide

To a stirred solution of 2-chloro-N-(2-(3-fluoro-4-sulfamoylphenyl)propan-2-yl)acetamide (4.02 g, 13.0 mmol) in EtOH (80 mL) and AcOH (16 mL) in a 250-mL round-bottom flask under nitrogen was added thiourea (1.19 g, 15.6 mmol). The resulting solution was stirred for 12 h at 80° C. The resulting mixture was concentrated and diluted with 200 mL of water. The resulting solution was extracted with 2×200 mL of EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. This resulted in 3.01 g (99.7%) of the title compound as a yellow solid. MS-ESI: 233 (M+1).

Step 4: Tert-butyl (2-(3-fluoro-4-sulfamoylphenyl)propan-2-yl)carbamate

To a stirred solution of 4-(2-aminopropan-2-yl)-2-fluorobenzenesulfonamide (3.01 g, 13.0 mmol) in THF (50 mL) in a 100-mL round-bottom flask under nitrogen was added TEA (2.63 g, 26.0 mmol), followed by the addition of (Boc)₂O (4.25 g, 19.5 mmol) in THF (10 mL) dropwise at 0° C. The resulting solution was stirred for 12 h at RT. The resulting solution was diluted with 100 mL of water. The resulting solution was extracted with 3×100 mL of EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 2.81 g (65.2%) of the title compound as yellow oil. MS-ESI: 333 (M+1).

Step 5: Tert-butyl (2-(4-(N-(tert-butyldiphenylsilyl)sulfamoyl)-3-fluorophenyl)propan-2-yl)carbamate

To a stirred solution of tert-butyl (2-(3-fluoro-4-sulfamoylphenyl)propan-2-yl)carbamate (2.80 g, 8.43 mmol) in THF (100 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% oil dispersion, 506 mg, 12.6 mmol) in portions at 0° C. The resulting solution was stirred for 20 min at RT. This was followed by the addition of TBDPSCl (2.78 g, 10.1 mmol) in THF (5 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 12 h at RT. The reaction was then quenched by the addition of 200 mL of water. The resulting solution was extracted with 3×200 mL of EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 3.0 g (62.4%) of the title compound as a yellow solid. MS-ESI: 571 (M+1).

Step 6: Tert-butyl(2-(4-(N-(tert-butyldiphenylsilyl)sulfamoyl)-fluorophenyl)propan-2-yl)(methyl)carbamate

To a stirred solution of tert-butyl (2-(4-(N-(tert-butyldiphenylsilyl)sulfamoyl)-3-fluorophenyl)propan-2-yl)carbamate (2.90 g, 5.08 mmol) in THF (100 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% oil dispersion, 406 mg, 10.2 mmol) in portions at 0° C. The resulting solution was stirred for 20 min at RT. This was followed by the addition of CH₃I (866 mg, 6.10 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 12 h at RT. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3×100 mL of EtOAc and the combined organic layer concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 2.0 g (67.3%) of the title compound as a yellow solid. MS-ESI: 585 (M+1).

Step 7: Tert-butyl(2-(4-(N′-(tert-butyldiphenylsilyl)sulfamidimidoyl)-3-fluorophenyl)propan-2-yl)-(methyl)carbamate

To a stirred solution of PPh₃Cl₂ (1.33 g, 4.0 mmol) in CHCl₃ (20 mL) in a 250-mL 3-necked round-bottom flask under nitrogen was added DIEA (1.29 g, 10.0 mmol) dropwise at 0° C. The resulting solution was stirred for 10 min at RT. To this was added a solution of tert-butyl(2-(4-(N-(tert-butyldiphenylsilyl)sulfamoyl)-3-fluorophenyl)propan-2-yl)(methyl) carbamate (1.17 g, 2.00 mmol) in CHCl₃ (20 mL) dropwise with stirring at 0° C. The resulting solution was allowed to react, with stirring, for an additional 30 min while the temperature was maintained at 0° C. in a water/ice bath. To the above NH₃ (g) was bubbled for 15 min at 0° C. The resulting solution was allowed to react, with stirring, for an additional 30 min at RT. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 703 mg (60.2%) of the title compound as an off-white solid. MS-ESI: 584 (M+1).

Intermediate 146

N′-(tert-butyldimethylsilyl)-4-(cyclopropyl(dimethylamino)methyl)benzenesulfonimidamide Step 1: (4-Bromophenyl)(cyclopropyl)methanamine

To a stirred solution of 4-bromobenzonitrile (10.0 g, 54.9 mmol) in THF (200 mL) in a 1000-mL 3-necked round-bottom flask under nitrogen was added cyclopropyl magnesium bromide (1 M in THF, 165 mL, 165 mmol) dropwise at 0° C. in 20 min. The resulting solution was stiffed for 5 h at 0° C. To this was added MeOH (200 mL) at 0° C. in 5 min. To the mixture was added NaBH₄ (10.4 g, 275 mmol), in portions at 0° C. over 10 min. The resulting solution was allowed to react, with stirring, for an additional 16 h at RT. The reaction was then quenched by the addition of 10 mL of water. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (20:1). This resulted in 9.79 g (78.9%) of the title compound as yellow oil. MS-ESI: 226/228 (M+1).

Step 2: 1-(4-Bromophenyl)-1-cyclopropyl-N,N-dimethylmethanamine

To a stirred solution of (4-bromophenyl)(cyclopropyl)methanamine (5.29 g, 23.4 mmol) in DCE (50 mL) in a 250-mL round-bottom flask under nitrogen was added HCOOH (10.8 g, 234 mmol) dropwise at RT. To this was added (HCHO)_(n) (3.54 g, 39.3 mmol) at RT. The resulting solution was stirred for 1 h at 80° C. The reaction was then quenched by the addition of 150 mL of water. The resulting solution was extracted with 3×200 mL of DCM. The organic layers were combined and dried over anhydrous Na₂SO₄. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (2:1). This resulted in 3.30 g (55.4%) of the title compound as a white solid. MS-ESI: 254/256 (M+1).

Steps 3-7 used similar procedures for converting compound 369″ to Intermediate 126 shown in Scheme 82 to afford intermediate 146 from compound 492″. MS-ESI: 368 (M+1).

TABLE 31 Intermediate 147 was prepared using similar procedures for converting compound 490″ to Intermediate 146 shown in Scheme 101 from appropriate starting materials. Exact Intermediate Mass # Structure IUPAC Name [M + H]⁺ Intermediate 147

N′-(tert-butyldimethylsilyl)-4- (1-(dimethylamino)-2,2,2- trifluoroethyl) benzenesulfonimidamide 396

Intermediate 148

N-(tert-butyldimethylsilyl)-6-(difluoromethyl)pyridine-3-sulfonimidamide Step 1: 5-Bromo-2-(difluoromethyl)pyridine

To a stirred solution of 5-bromopicolinaldehyde (1.86 g, 10.0 mmol) in THF (50 mL) in a 250-mL round-bottom flask was added DAST (3.22 g, 20.0 mmol) dropwise at 0° C. The resulting solution was stirred for 6 h at RT. The reaction was then poured into 100 mL of water/ice. The resulting solution was extracted with 3×200 mL of EtOAc and the organic layers combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. This resulted in 2.10 g (crude) of the title compound as yellow oil. MS-ESI: 208/210 (M+1).

Steps 2-5 used similar procedures for converting compound 369″ to intermediate 126 shown in Scheme 82 to afford intermediate 148 from compound 498″. MS-ESI: 322 (M+1).

Intermediate 103

tert-butyl (R)-((4-formylphenyl)(3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(oxo)-λ⁶-sulfanylidene)carbamate Step 1: ((4-bromobenzyl)oxy)(tert-butyl)dimethylsilane

Into a 500-mL round bottom flask was placed 4-bromobenzyl alcohol (15 g, 80.2 mmol), imidazole (12.01 g, 176.44 mmol) in DCM (270 mL). TBSCl (13.08 g, 84.21 mmol) was added in one portion and the mixture stirred overnight at RT. MeOH (10 mL) was added and the reaction mixture was stirred for 30 min. The mixture was transferred to a separatory funnel, washed with water (2×100 mL) and aq. NaHCO₃ (100 mL). The organic phase was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure affording the title compound (23.75 g, 98%) as a pale yellow oil. The crude product was used in the next step.

Step 2: (4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)magnesium bromide

Magnesium turnings (888 mg, 35.6 mmol) were suspended in a flame-dried 100-mL round bottom flask. Dry THF (10 mL) was added. A solution of ((4-bromobenzyl)oxy)(tert-butyl)dimethylsilane (10 g, 33.19 mmol) in 30 mL THF was prepared and was added to the Mg-containing flask via dropping funnel. The mixture was refluxed for 2 h then cooled to RT and left to settle overnight. The Grignard solution was titrated against a known quantity of menthol and a catalytic amount of 1,10-phenanthroline in THF. Final titer (average of two titrations) was 0.51 M.

Step 3: (S)-4-(((tert-butyldimethylsilyl)oxy)methyl)benzenesulfinamide

In a 100 mL round bottom flask, a solution of (4-(((tert-butyldimethylsilyl)oxy)methyl) phenyl)magnesium bromide (prepared using the procedure described in the step above; 0.86 M in THF, 27 mL, 23 mmol) was diluted with THF (71 mL) and cooled to −46° C. (acetonitrile-dry ice bath). The resulting milky suspension was added via cannula to a solution of (2R,3aS,8aR)-3-(mesitylsulfonyl)-3,3a,8,8a-tetrahydroindeno-[1,2-d][1,2,3]oxathiazole 2-oxide (5.88 g, 15.58 mmol; prepared using the procedure detailed in Org. Synth. 2006, 83, 131) in THF (68 mL) keeping the internal temperature of the mixture below −42° C. After addition, the reaction mixture was stirred at −46° C. for 1 hour. LiHMDS (1 M in toluene, 46.7 mL, 46.7 mmol) was added and the reaction mixture was warmed-up to 0° C. and stirred for 1 h. A saturated solution of NaHCO₃ (50 mL) was added and the mixture stirred for 15 min. EtOAc (150 mL) and half-saturated brine (50 mL) were added and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash chromatography with an isocratic mixture of 6% (10% NH₄OH in MeOH) in chloroform affording 2.3 g of the title compound (75%) as an off-white solid. MS-ESI: 286.1 (M+1).

Step 4: tert-butyl (S)-((4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)sulfinyl)carbamate

In a 500-mL round bottom flask was dissolved (S)-4-(((tert-butyldimethylsilyl)oxy)methyl) benzenesulfinamide (12.0 g, 42.03 mmol) in THF (350 ml). n-BuLi (2.5 M in THF, 35.2 ml, 88.3 mmol) was then added at −78° C. The mixture was stirred at the same temperature for 10 min. A solution of di-tert-butyl carbonate (9.63 g, 44.13 mmol) in THF (21 mL) was added in one portion and the reaction mixture warmed up to 0° C. with stirring. The solution was stirred at 0° C. for 1 h. Formic acid (98%, 4.5 mL, 88.3 mmol) was added, the reaction mixture was stirred 10 min and then diluted with EtOAc (350 mL). Half-saturated brine (100 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (2×200 mL). The organic phases were combined, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude was purified by flash chromatography using a gradient of 5-10% MeOH in DCM affording 12.3 g of the title compound (76%) as a transparent syrup. MS-ESI: 286.0 (M-Boc).

Step 5: tert-butyl (S)-(amino(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)(oxo)-λ⁶-sulfanylidene)-carbamate

To a cooled (−10° C.) solution of tert-butyl (S)-((4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl) sulfinyl)carbamate (12.20 g, 31.9 mmol) in THF (50 ml) in a 100-mL round bottom flask was added TCCA (2.52 g, 10.84 mmol, 0.34 eq) in portions. Internal temperature was kept below −5° C. The mixture was stirred at 0° C. for 60 min, followed by 1 h at RT. Concentrated ammonium hydroxide (14 M, 34.2 mL) was added dropwise and the reaction left to warm to RT overnight. The reaction mixture was diluted with ethyl acetate (400 mL) and washed the organic phase with half-saturated brine (100 mL). The aqueous phase was extracted with EtOAc (300 ml) and the combined organic phases were dried (Na₂SO₄), evaporated and the crude was purified by flash chromatography using a gradient of 5-50% EtOAc in hexanes to afford 10 g of the title compound (78%) as a light brown syrup. MS-ESI: 423.1 (M+Na).

Step 6: tert-butyl (R)-((3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(4-(hydroxymethyl)phenyl) (oxo)-λ⁶-sulfanylidene)carbamate

To a 0° C. (ice bath) solution of tert-butyl (S)-(amino(4-(((tert-butyldimethylsilyl)oxy)methyl) phenyl)(oxo)-λ⁶-sulfanylidene)carbamate (9.77 g, 24.39 mmol) in THF (244 ml) was added dropwise potassium tert-butoxide (1 M in THF, 25.6 ml, 25.6 mmol) keeping the internal temperature below −2.2° C. The reaction mixture was stirred for 1 hour at 0° C. A solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (5.1 g, 25.61 mmol) in THF (66 mL) was added dropwise and the mixture stirred at RT for 1 h, then formic acid was added (1 mL, 25.61 mmol) and the solution stirred for 10 min. The reaction mixture was diluted with EtOAc (300 mL) and washed with half-saturated brine (100 mL). The aqueous phase was extracted with EtOAc (250 mL) and the combined organic phases were dried over anhydrous Na₂SO₄, and concentrated under reduced pressure affording the crude TBS ether (13.95 g).

The TBS ether was dissolved in MeOH (211 mL), cooled to 0° C. and aqueous HCl (2 M, 280 mL, 558.67 mmol) was added and the reaction mixture was stirred 2 hours at 0° C. The crude mixture was diluted with EtOAc (400 mL), transferred to a separatory funnel and washed with water (100 mL). A white solid precipitated out of solution and the heterogeneous mixture was filtered. The solid was washed with water (100 mL) and EtOAc (100 mL), and dried overnight at low pressure affording 5.96 g of the title compound (53% over two steps) as a white solid. MS-ESI: 486.3 (M+1).

Step 7: tert-butyl (R)-((4-formylphenyl)(3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(oxo)-λ⁶-sulfanylidene)carbamate

In a flame-dried 500-mL round bottom flask, MnO₂ (12 g, 143 mmol) was suspended in dry toluene (250 mL) under an argon atmosphere. The solvent was removed under reduced pressure at 50° C., then the flask was kept at high vacuum pump for 1 h. A solution of tert-butyl (R)-((3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(4-(hydroxymethyl)phenyl)(oxo)-λ⁶-sulfanylidene)carbamate (1.5 g, 3.089 mmol) in dry THF (130 mL) was added to the flask containing the MnO₂ under an argon atmosphere. The resulting mixture was vigorously stirred at RT for 3 h. The mixture was filtered through a Celite pad which was washed with MeOH (150 mL) and the filtrate and wash were concentrated under reduced pressure at 30° C., resulting in isolation of 1.22 g of the title compound as a pale yellow solid (82%). MS-ESI: 484.4 (M+1).

Intermediate 150

Tert-butyl (2-(4-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)phenyl)propan-2-yl)(methyl)carbamate Step 1: Tert-butyl (2-(4-bromophenyl)propan-2-yl)carbamate

To a stirred solution of 2-(4-bromophenyl)propan-2-amine (5.0 g, 23.4 mmol) in DCM (60 mL) in a 250-mL round-bottom flask was added TEA (4.73 g, 46.8 mmol), followed by the addition of (Boc)₂O (8.94 g, 41.0 mmol) in DCM (10 mL) dropwise at 0° C. The resulting solution was stirred for 15 h at RT. The solution was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (3/7). This resulted in 6.81 g (92.7%) of the title compound as a yellow solid. MS-ESI: 314/316 (M+1).

Step 2: Tert-butyl (2-(4-bromophenyl)propan-2-yl)(methyl)carbamate

To a stirred solution of tert-butyl (2-(4-bromophenyl)propan-2-yl)carbamate (3.14 g, 10.0 mmol) in THF (100 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% oil dispersion, 800 mg, 20.0 mmol) in portions at 0° C. The resulting solution was stirred for 20 min at RT. This was followed by the addition of CH₃I (4.26 g, 30.0 mmol) dropwise with stirring at 0° C. The resulting solution was allowed to react, with stirring, for an additional 16 h at RT. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3×100 mL of EtOAc and the organic layers were combined then dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1/4). This resulted in 2.47 g (75.2%) of the title compound as a yellow solid. MS-ESI: 328/330 (M+1).

Steps 3-7 used similar procedures for converting compound 369″ to intermediate 126 shown in Scheme 82 to afford intermediate 150 from compound 515″. MS-ESI: 442 (M+1).

Intermediate 151

N′-(tert-butyldimethylsilyl)-4-((methyl(2,2,2-trifluoroethyl)amino)methyl)benzenesulfonimidamide Step 1: N-(4-bromobenzyl)-2,2,2-trifluoro-N-methylethan-1-amine

To a stirred solution of 1-(4-bromophenyl)-N-methylmethanamine (3.90 g, 19.5 mmol) in DCM (200 mL) in a 500-mL round-bottom flask under nitrogen was added TFA (6.67 g, 58.5 mmol) and PhSiH₃ (4.21 g, 39.0 mmol) at RT. The resulting solution was stirred for 12 h at 40° C. in an oil bath. The reaction mixture was cooled to 0° C. with a water/ice bath. The pH value of the solution was adjusted to 7 with NaOH (1 M). The resulting solution was extracted with 3×200 mL of DCM, the combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:10). This resulted in 3.80 g (69.1%) of the title compound as yellow oil. MS-ESI: 282 (M+1).

Steps 2-5 used similar procedures for converting compound 369″ to intermediate 126 shown in Scheme 82 to afford intermediate 151 from compound 521″. MS-ESI: 396 (M+1).

TABLE 32 Intermediate 152 was prepared using similar procedures for converting compound 520″ to Intermediate 151 shown in Scheme 105 from appropriate starting materials. Exact Intermediate Mass # Structure IUPAC Name [M + H]⁺ Intermediate 152

N′-(tert-butyldimethylsilyl)-4-(((2,2- difluoroethyl)(methyl)amino) methyl)benzenesulfonimidamide 378

Intermediate 153

N′-(tert-butyldimethylsilyl)benzenesulfonimidamide

Steps 1-2 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford intermediate 153 from compound 525″. MS-ESI: 271 (M+1).

Intermediate 154

3-Formyl-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide Step 1: 3-(Hydroxymethyl)benzenesulfonamide

To a stirred solution of 3-sulfamoylbenzoic acid (10 g, 49.7 mmol) in THF (200 mL) in a 1000 mL 3-necked round-bottom flask under nitrogen was added BH₃-THF (1 M, 198 mL, 198 mmol) dropwise at 0° C. in an ice bath. The resulting solution was stirred for 30 min at 0° C. and then allowed to react, with stirring, for an additional 4 h at RT. The reaction was then quenched by the addition of 200 mL of MeOH. The resulting solution was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 8.8 g (94.6%) of the title compound as yellow oil. MS-ESI: 186 (M−1).

Step 2: 3-(((Tert-butyldimethylsilyl)oxy)methyl)benzenesulfonamide

To a stirred solution of 3-(hydroxymethyl)benzenesulfonamide (5.0 g, 26.7 mmol) in THF (50 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% oil dispersion, 1.28 g, 53.4 mmol) and TBSCl (6.04 g, 40.1 mmol) in portions at 0° C. in a water/ice bath. The resulting solution was stirred for 12 h at RT. The reaction was then quenched by the addition of 100 mL of water/ice. The resulting solution was extracted with 3×150 mL of EtOAc and the organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (2:1). This resulted in 5.8 g (72%) of the title compound as a white solid. MS-ESI: 302 (M+1).

Steps 3-5 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford compound 532″ from compound 529″. MS-ESI: 415 (M+1).

Step 6: N-(tert-butyldimethylsilyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide

To a stirred solution of N′-(tert-butyldimethylsilyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)benzene-sulfonimidamide (2.0 g, 4.82 mmol) in THF (20 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added NaH (60% oil dispersion, 0.23 g, 9.64 mmol) in portions at 0° C. The resulting solution was stirred for 15 min at 0° C. in a water/ice bath. Then to the stirred solution was added 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (0.96 g, 4.82 mmol) in THF (5 mL) dropwise at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 15 mL of water/ice. The resulting solution was extracted with 3×50 mL of EtOAc and the organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. This resulted in 2.25 g (75.9%) of the title compound as a white solid. MS-ESI: 614 (M+1).

Step 7: N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-hydroxymethyl)benzenesulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)benzenesulfonimidamide (500 mg, 0.81 mmol) in THF (10 mL) in a 100-mL round-bottom flask under nitrogen was added HCl in 1,4-dioxane (4 M, 10.0 mL, 40.0 mmol) dropwise at 0° C. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10/1). This resulted in 125 mg (39.8%) of the title compound as a white solid. MS-ESI: 386 (M+1).

Step 8: 3-Formyl-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide

To a stirred solution of N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(hydroxymethyl)benzene-sulfonimidamide (120 mg, 0.31 mmol) in THF (10 mL) in a 50-mL round-bottom flask under nitrogen was added MnO₂ (541 mg, 6.23 mmol) at RT. The resulting solution was stirred for 12 h at RT. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 80 mg (67.0%) of the title compound as a white solid. MS-ESI: 384 (M+1).

Intermediate 155

N′-(tert-butyldimethylsilyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide Step 1: 6:7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine

To a stirred solution of 1,2-dihydro-3H-pyrazol-3-one (42 g, 500 mmol) in DMF (500 mL) in a 1 L 3-neck flask was added K₂CO₃ (138 g, 1.0 mol) in portions and 1,3-dibromopropane (111 g, 550 mmol) was added dropwise at RT. The resulting mixture was stirred for 16 h at 130° C. under nitrogen. The insoluble was filtered out, the filtrate was poured into 1500 mL of water, extracted with 3×500 mL of EtOAc. The organic layers combined and dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (20:1) to afford 24.8 g (40%) the title compound as a yellow solid. MS-ESI: 125 (M+1).

Step 2: 6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonyl chloride

To a stirred solution of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (24 g, 194 mmol) in chlorosulfonic acid (143 mL) in a 1000-mL 3-necked round-bottom flask under nitrogen. The resulting solution was stirred for 16 h at 80° C. under nitrogen. The reaction mixture was poured into 1500 mL of water/ice very slowly, extracted with 3×500 mL of EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was washed with 300 mL of PE. This resulted in the title compound (28.1 g, 65.0%) as a yellow solid. MS-ESI: 223/225 (M+1).

Step 3: 6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide

To a stirred solution of ammonia (30% wt., 100 mL) in a 1000-mL 3-necked round-bottom flask under nitrogen was added 6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazine-3-sulfonyl chloride (28 g, 126 mmol) in THF (100 mL) dropwise at RT. The resulting solution was stirred for 16 h at 60° C. under nitrogen. The organic solvent was removed by centration under reduced pressure and then extracted with 3×500 mL of EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was eluted from gel column with PE/EtOAc (1:1). This resulted in 16.9 g (66%) of the title compound as a light yellow solid. MS-ESI: 202 (M−1).

Steps 4-6 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford intermediate 155 from compound 538″. MS-ESI: 317 (M+1).

Intermediate 156

(6R)-N′-(tert-butyldiphenylsilyl)-6-((tert-butyldiphenylsilyl)oxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide Step 1: 1,2-Dihydropyrazol-5-one

To a 5 L 4-neck flask containing a solution of methyl (E)-3-methoxyacrylate (2000 g, 17.2 mol) in MeOH (2.0 L) was added hydrazine hydrate (921 g, 18.4 mol) dropwise at RT under nitrogen. The resulting mixture was stirred for 90 min at 60° C. under nitrogen. The resulting mixture was concentrated under reduced pressure. This resulted in the title compound (1467 g, 68% wt, yield 69%) as an off-white solid. MS-ESI: 85 (M+1).

Step 2: 2-Acetyl-1,2-dihydropyrazol-5-one

To a 10 L 4-neck flask containing a solution of 1,2-dihydropyrazol-5-one (1467 g, 68% wt, 11.9 mol) in pyridine (6.0 L) was added Ac₂O (1214 g, 11.9 mol) at RT under nitrogen. The resulting mixture was stirred for 1.5 h at 95° C. under nitrogen. The resulting mixture was concentrated under reduced pressure. The residue was slurry with MeOH (1×3000 mL). The resulting mixture was filtered, the filter cake was washed with MeOH (1×500 mL). The filter cake was dried under reduced pressure. This resulted in the title compound (1630 g, 78% wt, 85%) as an off-white solid. MS-ESI: 127 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (d, J=3.0 Hz, 1H), 6.00 (d, J=3.0 Hz, 1H), 2.48 (s, 3H), 2.44 (s, 1H).

Step 3: (R)-2-acetyl-1-(oxiran-2-ylmethyl)-1,2-dihydropyrazol-5-one

To a 10 L 4-neck flask containing a solution of 2-acetyl-1,2-dihydropyrazol-5-one (400 g, 78% wt, 3.17 mol) and R-glycidol (246 g, 3.33 mol) in THF (4.0 L), to the stirred solution was added PPh₃ (915 g, 3.49 mol). To the above mixture was added TMAD (705 g, 3488 mmol) in portions at 0° C. The resulting mixture was stirred for additional 1 h at RT. The resulting mixture was quenched with 1×4.0 L of water. The aqueous layer was extracted with EtOAc (3×1.0 L). The organic layers were combined and washes with brine (1 L), dried over Na₂SO₄ and concentrated under reduced pressure. The crude was slurry in PE/EtOAc (10:1) (16 L) for 4 h. The resulting mixture was filtered. The filter cake was washed with PE/EtOAc (10:1) (1×1000 mL). The filtrate was concentrated under reduced pressure. This resulted in the title compound (470 g, 84% wt, 87%) as an off-white solid. MS-ESI: 183 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (d, J=3.0 Hz, 1H), 6.27 (d, J=3.0 Hz, 1H), 4.56 (dd, J=11.8, 2.7 Hz, 1H), 4.02 (dd, J=11.8, 6.8 Hz, 1H), 3.40-3.34 (m, 1H), 2.86 (dd, J=5.1, 4.3 Hz, 1H), 2.74 (dd, J=5.1, 2.6 Hz, 1H), 2.54 (s, 3H).

Step 4: (R)-2-acetyl-1-(3-chloro-2-hydroxypropyl)-1,2-dihydropyrazol-5-one

To a 10 L 3-neck flask was placed a solution of (R)-2-acetyl-1-(oxiran-2-ylmethyl)-1,2-dihydropyrazol-5-one (500 g, 84% wt, 2.74 mol) in THF (2.5 L), to the stirred solution was added AcOH (494 g, 8233 mmol) dropwise and LiCl (186 g, 4391 mmol) in portions at 0° C. under nitrogen. The resulting mixture was stirred for 16 h at RT under nitrogen. The reaction was quenched with water at RT. The aqueous layer was extracted with EtOAc (3×3.0 L). The organic layers were combined and washed with 2×3.0 L of sat. NaHCO₃ and 5.0 L of brine. The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. This resulted in the title compound (552 g, 82% wt, yield 90%) as an off-white solid. MS-ESI: 219 (M+1). ¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J=3.0 Hz, 1H), 6.02 (d, J=3.0 Hz, 1H), 4.44 (d, J=5.0 Hz, 2H), 4.29-4.23 (m, 1H), 3.81-3.67 (m, 2H), 2.61 (s, 3H).

Step 5: (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol

To a 10 L 3-neck flask was placed a solution of (R)-2-acetyl-1-(3-chloro-2-hydroxypropyl)-1,2-dihydropyrazol-5-one (500 g, 82% wt, 2.29 mol) in DIVIF (5.0 L), to the stirred solution was added K₂CO₃ (948 g, 6.86 mol) under nitrogen. The resulting mixture was stirred for 16 h at 135° C. under nitrogen and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (20:1) to afford (152 g, yield 58%) of the title compound as an off-white solid. MS-ESI: 141 (M+1). ¹H NMR (400 MHz, MeOH-d₄) δ 7.11 (d, J=2.1 Hz, 1H), 5.31 (d, J=2.1 Hz, 1H), 4.19-4.12 (m, 1H), 4.12-3.98 (m, 3H), 3.90-3.81 (m, 1H).

Step 6: (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl acetate

To a stirred solution of (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (55.0 g, 392 mmol) in MeCN (825 mL) in a 2-L 3-necked round-bottom flask under nitrogen was added pyridine (93.1 g, 1.18 mol) and DMAP (4.79 g, 39.2 mmol). This was followed by the addition of acetyl chloride (43.1 g, 549 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at RT. LCMS showed reaction was completed. The resulting mixture was concentrated directly. The residue was eluted from silica gel with EtOAc/PE (1:4). This resulted in 58 g (81%) of the title compound as a light yellow solid. MS-ESI: 183 (M+1). ¹H NMR (400 MHz, CDCl₃) δ 7.39 (d, J=2.0 Hz, 1H), 5.57 (d, J=2.0 Hz, 1H), 5.45-5.36 (m, 1H), 4.49-4.41 (m, 1H), 4.40-4.27 (m, 2H), 4.24 (dd, J=12.1, 1.5 Hz, 1H), 2.14 (s, 3H).

Step 7: (R)-6-acetoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid

To a stirred solution of (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl acetate (58.0 g, 318 mmol) in DCM (120 mL) in a 2-L 3-necked round-bottom flask under nitrogen was added chlorosulfonic acid (81.3 g, 700 mmol) dropwise at 0° C. The resulting solution was stirred for 12 h at RT. LCMS showed the conversion was completed. The reaction mixture was used directly in the next step. MS-ESI: 263 (M+1).

Step 8: (R)-3-(chlorosulfonyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-6-yl acetate

To a stirred solution of (R)-6-acetoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid in DCM (crude from step 7) in a 2-L 3-necked round-bottom flask under nitrogen was added pyridine (55.1 g, 696 mmol) dropwise at 0° C. To this was added PCl₅ (144 g, 696 mmol) in portions at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 1 L of water/ice. The resulting solution was extracted with 3×300 mL of EtOAc. The resulting mixture was washed with 2 ×500 ml of NaHCO₃ and 1 ×500 mL of H₂O. The resulting mixture was washed with 1×500 mL of NaCl (aq.). The mixture was dried over anhydrous Na₂SO₄ and concentrated under vacuum. This resulted in 76 g (crude) of the title compound as a light yellow solid. MS-ESI: 281/283 (M+1).

Step 9: (R)-6-hydroxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide

To a stirred solution of NH₃ in THF (1M, 730 ml) in a 3-L round-bottom flask was added (R)-3-(chloro-sulfonyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazin-6-yl acetate (73.0 g) in several batches. The flask was then filled with NH₃ (balloon). The resulting solution was stirred overnight at 40° C. in an oil bath. After reaction completed, the solids were filtered out. The filtrate was concentrated. The residue was diluted with NH₃ (7 M in MeOH, 730 mL). The resulting solution was stirred for 2 h at RT. LC showed the reaction was complete. The MeOH solution was concentrated under reduced pressure to a final volume of about 100 mL. Et₂O (360 ml) was charged to the resulting solution and kept stirring for 30 min. The mixture was filtered, and the cake washed with Et₂O (100 mL). The white solid was dried under vacuum. This resulted in 37 g (53% for 3 steps) of the title compound as a white solid. MS-ESI: 220 (M+1). ¹H NMR (300 MHz, DMSO-d₆) δ 7.48 (s, 1H), 7.06 (s, 2H), 5.64 (d, J=2.3 Hz, 1H), 4.30 (s, 3H), 4.30-4.18 (m, 1H), 4.00-3.90 (m, 1H).

Step 10: (R)-N-(tert-butyldiphenylsilyl)-6-((tert-butyldiphenylsilyl)oxy)-6,7-dihydro-5H-pyrazolo[5,1-b]-[1,3]oxazine-3-sulfonamide

To a stirred solution of (R)-6-hydroxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazine-3-sulfonamide (500 mg, 2.28 mmol) in DMF (20 mL) in a 50-mL round-bottom flask was added DBU (2.08 g, 13.7 mmol) and TBDPSCl (5.02 g, 18.2 mmol) at 0° C. The resulting solution was stirred for 2 h at RT and then diluted with 30 mL of H₂O. The resulting solution was extracted with 3×100 mL of EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 530 mg (33.3%) of the title compound as a solid. MS-ESI: 696 (M+1).

Step 11: (6R)-N′-(tert-butyldiphenylsilyl)-6-((tert-butyldiphenylsilyl)oxy)-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonimidamide

To a stirred solution of PPh₃Cl₂ (759 mg, 2.28 mmol) in DCE (30 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added DIEA (492 mg, 3.81 mmol) at 0° C. The resulting solution was stirred for 10 min at RT. Then (R)-N-(tert-butyldiphenylsilyl)-6-((tert-butyldiphenylsilyl)oxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazine-3-sulfonamide (530 mg, 0.76 mmol) in CHCl₃ (10 mL) was added at 0° C. The resulting solution was stirred for 30 min at 0° C. Then NH₃ (g) was bubbled to the reaction mixture for 15 min at 0° C. The resulting solution was stirred for 2 h at RT. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 400 mg (75.6%) of the title compound as a white solid. MS-ESI: 695 (M+1).

Intermediate 157

(6R)-N′-(tert-butyldimethylsilyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide Step 1: (R)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine

To a stirred solution of (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (40 g, 285 mmol) in DMF (400 mL) in a 1 L 4-neck round-bottom flask was added NaH (60% oil dispersion, 13.7 g, 342 mmol) in portions at 0° C. The resulting mixture was stirred for 1 h at RT. To the above mixture was added MeI (48.7 g, 343 mmol) dropwise at RT. The resulting mixture was stirred for additional 2 h at RT. The reaction was quenched with AcOH (3.66 g, 57.1 mmol) at 0° C. and concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (1:2) to afford the title compound (34.6 g, 79%) as a light yellow solid. MS-ESI: 155 (M+1).

Steps 2-4 used similar procedures for converting compound 547″ to compound 550″ shown in Scheme 109 to afford intermediate 159 from compound 562″. MS-ESI: 232 (M−1).

Steps 5-6 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford intermediate 157 from compound 555″. MS-ESI: 347 (M+1).

Intermediate 158

Tert-butyl ((6R)-3-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate

Steps 1-5 used similar procedures for converting compound 541″ to compound 546″ shown in Scheme 109 to afford compound 559″ from compound 541″. MS-ESI: 141 (M+1).

Step 6: (S)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl methanesulfonate

To a stirred solution of (S)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (40 g, 285 mmol) in pyridine (280 mL) in a 500 mL 3-neck flask under nitrogen was added MsCl (39 g, 343 mmol) dropwise at RT. The resulting mixture was stirred for 30 min at RT. The resulting mixture was concentrated under reduced pressure. The crude was diluted with 500 mL of water. The resulting mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with water (3×200 mL) and brine 1×100 mL, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (57 g, 92%) as an off-white solid. MS-ESI: 219 (M+1).

Step 7: (R)-6-azido-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine

To a stirred solution of (S)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl methanesulfonate (46 g, 211 mmol) in DMF (313 mL) in a 1 L 3-neck flask under nitrogen was added NaN₃ (21 g, 316 mmol) at RT. The resulting mixture was stirred for 6 h at 80° C. LCMS showed reaction was complete. This was used directly in the next step. MS-ESI: 166 (M+1).

Step 8: (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-amine

To a stirred solution of (R)-6-azido-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine in DMF from the last step was added MeOH (313 mL) followed by Pd/C (10% wt., 10 g) under nitrogen. The mixture was hydrogenated at RT for 5 h under hydrogen atmosphere using a hydrogen balloon. LCMS showed reaction was complete. The mixture was filtered through a pad of Celite and concentrated under reduced pressure to remove low boiling solvent. This resulted in the title compound in DMF solution which was used directly in the next step. MS-ESI: 140 (M+1).

Step 9: Tert-butyl (R)-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate

To a stirred solution of (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-amine in DMF from the last step was added MeOH (313 mL) followed by TEA (50 g, 496 mmol) and di-tert-butyl dicarbonate (79 g, 364 mmol) at RT under nitrogen. The resulting mixture was stirred for 16 h at RT. The resulting mixture was quenched with 500 mL of water. The resulting mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with H₂O (2×600 mL) and brine (1×600 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (45.9 g, 91%, for 3 steps) as an off-white solid. MS-ESI: 240 (M+1).

Step 10: Tert-butyl (R)-(3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate

To a stirred solution of tert-butyl (R)-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazin-6-yl)carbamate (140 g, 585 mmol) in MeCN (2.1 L) in a 3 L 3-neck flask under nitrogen was added NBS (115 g, 644 mmol) at 0° C. The resulting mixture was stirred for 2 h at RT. The resulting mixture was diluted with 2000 mL of water. The resulting mixture was extracted with EtOAc (3×800 mL). The combined organic layers were washed with brine (1×800 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (167 g, 90%) as an off-white solid. MS-ESI: 318/320 (M+1).

Step 11: Tert-butyl (R)-(3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate

To a stirred solution of tert-butyl(R)-(3-bromo-6,7-dihydro-5H-pyrazolo -[5,1-b][1,3]oxazin-6-yl)carbamate (170 g, 534 mmol) in DMF (1.19 L) in a 3 L 3-neck flask under nitrogen was added sodium hydride (60% oil dispersion, 26 g, 650 mmol) in portions at 0° C. The mixture was stirred for 1 h at 0° C. Then MeI (379 g, 2.67 mol) was added and the mixture was allowed to warm to RT and stirred for 2 h. The reaction mixture was quenched by water and extracted with EtOAc (3*800 mL), the organic layers were washed with H₂O (3×500 mL) and brine (1×800 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (8:1) to afford the title compound (153 g, 86%) as an off-white solid. MS-ESI: 332/334 (M+1).

Step 12: Tert-butyl(R)-(3-(benzylthio)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl) carbamate

To a stirred solution of tert-butyl(R)-(3-bromo-6,7-dihydro-5H-pyrazolo -[5,1-b][1,3] oxazin-6-yl)(methyl)carbamate (130 g, 391 mmol) in THF (1.3 L) in a 3 L 3-neck flask under nitrogen was added n-BuLi (188 mL, 470 mmol, 2.5 mol/L) dropwise at −78° C. The resulting mixture was stirred for 1 h at −78° C. To the above mixture was added bis(phenylmethyl) disulfide (145 g, 587 mmol) in THF (300 mL) dropwise at −78° C. The resulting mixture was stirred for additional 2 h at RT. The reaction was quenched by the addition of sat. NH₄Cl (aq.) (500 mL) at RT. The resulting mixture was extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (1×800 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (6:1) to afford the title compound (106 g, 72%) as an off-white solid. MS-ESI: 376 (M+1).

Step 13: Tert-butyl (R)-(3-(chlorosulfonyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl) carbamate

To a stirred solution of tert-butyl (R)-(3-(benzylthio)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)-(methyl) carbamate (110 g, 293 mmol) in AcOH (3.67 L)/H₂O (1.83 L) in a 10 L 3-neck flask under nitrogen was added NCS (155 g, 1.17 mol) in portions at 0° C. The resulting mixture was stirred for 1 h at RT. The reaction was quenched with water/ice at RT. The resulting mixture was extracted with MTBE (3×1 L). The combined organic layers were washed with water (2×1.0 L), NaHCO₃ (L) and brine (1×1 L), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (80 g, crude) as a yellow solid. MS-ESI: 374 (M+Na).

Step 14: Tert-butyl (R)-methyl(3-sulfamoyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate

To a stirred solution of tert-butyl (R)-(3-(chlorosulfonyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl) carbamate (80 g, 227 mmol) in NH₃ in THF (1 M, 800 mL, 800 mmol) in a 2 L 3-neck flask under nitrogen. The flask was then filled with NH₃ (balloon). The resulting mixture was stirred for overnight at 60° C. The reaction mixture was quenched by water and extracted with MTBE (3*800 mL), the organic layers were washed with H₂O (3×500 mL) and brine (1×800 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The precipitated solid was slurry with MTBE (1×100 mL). This resulted in the title compound (36 g, for 2 steps) as an off-white solid. MS-ESI: 333 (M+1).

Steps 15-16 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford intermediate 158 from compound 568. MS-ESI: 446 (M+1).

Intermediate 159

N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)pyridine-3-sulfonimidamide

Step 1 used similar procedures for converting compound 406″ to compound 407″ shown in Scheme 87 to afford compound 571″ from compound 570″. MS-ESI: 215/217 (M+1).

Steps 2-7 used similar procedures for converting compound 369″ to intermediate 126 shown in Scheme 82 to afford intermediate 159 from compound 571″. MS-ESI: 330 (M+1).

Intermediate 160

N′-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Step 1 used similar procedures for converting compound 406″ to compound 407″ shown in Scheme 87 to afford compound 87 from compound 577″. MS-ESI: 144 (M+1).

Steps 2-3 used similar procedures for converting compound 369″ to compound 371″ shown in Scheme 82 to afford compound 85 from compound 87. MS-ESI: 223 (M+1).

Step 4: 2-(Prop-1-en-2-yl)thiazole-5-sulfonamide

To a stirred solution of 2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide (50 g, 225 mmol,) in trifluoromethanesulfonoperoxoic acid (60 mL) in a 1-L round-bottom flask under nitrogen was added TFA (60 mL). The resulting solution was stirred for 16 h at 50° C. in an oil bath. The pH value of the solution was adjusted to 8 with NaOH (3% wt.) solution. The resulting solution was extracted with 3×500 mL of DCM and the organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 10 g (21%) of the title compound as an off-white solid. MS-ESI: 205 (M+1).

Step 5: 2-(1,2-Dihydroxypropan-2-yl)thiazole-5-sulfonamide

Into a 500-mL round-bottom flask, was placed 2-(prop-1-en-2-yl)thiazole-5-sulfonamide (10 g, 49 mmol) in t-BuOH (40 mL) and acetone (40 mL), to the stirred solution was added NMO (11.5 g, 97.9 mmol) and the resulting solution was stirred for 15 min at RT. Then to this was added a solution of OsO₄ (1.24 g, 4.9 mmol) in H₂O (60 mL) at RT. The resulting solution was stirred overnight at RT. The reaction was then quenched by the addition of the saturation solution of Na₂S₂O₃ (50 mL). The resulting solution was extracted with EtOAc (3×100 mL). The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was eluted from silica gel with MeOH/DCM (7:100). This resulted in 5 g (43%) of the title compound as yellow oil. MS-ESI: 239 (M+1).

Steps 6-9 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford intermediate 160 from compound 579″. MS-ESI: 466 (M+1).

TABLE 33 The Intermediate 161 was prepared using similar procedures for converting compound 577″ to Intermediate 160 shown in Scheme 113 from appropriate starting materials. Exact Intermediate Mass # Structure IUPAC Name [M + H]⁺ Intermediate 161

N′-(tert-butyldimethylsilyl)-5-(1-((tert-butyldimethylsilyl)oxy)- 2-hydroxypropan-2-yl)-3-fluorothiophene-2-sulfonimidamide 483

Intermediate 162

N′-(tert-butyldimethylsilyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

Steps 1-3 used similar procedures for converting compound 410″ to compound 413″ shown in Scheme 88 to afford compound 586″ from compound 583″. MS-ESI: 262 (M+1).

Step 4 used similar procedures for converting compound 416″ to compound 417″ shown in Scheme 89 to afford compound 587″ from compound 586″. MS-ESI: 220 (M+1).

Steps 5-6 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford intermediate 167 from compound 594″. MS-ESI: 447 (M+1).

Intermediate 163

N-(tert-butyldiphenylsilyl)-4-(1-(difluoromethoxy)ethyl)benzenesulfonimidamide

Step 1 used similar procedures for converting intermediate 550″ to compound 551″ shown in Scheme 109 to afford compound 590″ from compound 589″. MS-ESI: 438 (M+1).

Step 2: N-(tert-butyldiphenylsilyl)-4-(1-hydroxyethyl)benzenesulfonamide

To a stirred solution of 4-acetyl-N-(tert-butyldiphenylsilyl)benzenesulfonamide (12 g, 27.5 mmol) in MeOH (100 mL) in a 500-mL round-bottom flask under nitrogen was added NaBH₄ (2.09 g, 54.9 mmol). The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 200 mL of water. The resulting solution was extracted with 3×200 mL of EtOAc and the organic layers were combined and concentrated under vacuum. This resulted in 8.0 g of the title compound as a yellow solid. MS-ESI: 440 (M+1).

Step 3: N-(tert-butyldiphenylsilyl)-4-(1-(difluoromethoxy)ethyl)benzenesulfonamide

To a stirred solution of N-(tert-butyldiphenylsilyl)-4-(1-hydroxyethyl)benzenesulfonamide (3.5 g, 7.97 mmol) in DCM (50 mL) and H₂O (50 mL) in a 250-mL round-bottom flask under nitrogen was added KOAc (3.12 g, 31.9 mmol) and (bromodifluoromethyl)trimethylsilane (6.47 g, 3.24 mmol). The resulting solution was stirred for 24 h at RT. The resulting solution was extracted with 3×100 mL of DCM and the organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel column with PE/EtOAc (3:1) to afford the title compound (2.81 g, yield 72%) as an off-white solid MS-ESI: 490 (M+1).

Step 4 used similar procedures for converting compound 362″ to Intermediate 124 shown in Scheme 80 to afford Intermediate 163 from compound 592″. MS-ESI: 489 (M+1).

Intermediate 164

6-Cyclopropyl-5-methyl-2,3-dihydro-1H-inden-4-amine Step 1: 6-Bromo-2,3-dihydro-1H-inden-5-amine

To a stirred solution of 2,3-dihydro-1H-inden-5-amine (5.0 g, 37.5 mmol) in MeCN (300 mL) in a 500-mL round-bottom flask under nitrogen was added a solution of NBS (6.68 g, 37.5 mmol) in MeCN/THF (1:1) (50 mL) dropwise at 0° C. The resulting solution was stirred for 1 h at 0° C. in a water/ice bath. The reaction was then quenched by the addition of 100 mL of sat. NaHCO₃ (aq). The resulting solution was extracted with 3×100 mL of EtOAc and the organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:20). This resulted in 7.0 g (87.9%) of the title compound as purple oil. MS-ESI: 212/214 (M+1).

Step 2: 6-Bromo-4-nitro-2,3-dihydro-1H-inden-5-amine

To a stirred solution of 6-bromo-2,3-dihydro-1H-inden-5-amine (1.92 g, 9.05 mmol) in cc. H₂SO₄ (10 mL) in a 50-mL round-bottom flask was added KNO₃ (1.1 g, 10.9 mmol) at 0° C. The resulting solution was stirred for 16 h at RT. The resulting solution was poured into 100 mL of water/ice slowly. The pH value of the solution was adjusted to 8 with sat. NaHCO₃ (aq.). The resulting solution was extracted with 3×100 mL of EtOAc. The combined organic phase was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 980 mg (42.1%) of the title compound as a red solid. MS-ESI: 256/258 (M+1).

Step 3: 6-Cyclopropyl-4-nitro-2,3-dihydro-1H-inden-5-amine

To a stirred solution of 6-bromo-4-nitro-2,3-dihydro-1H-inden-5-amine (0.98 g, 3.81 mmol) in toluene (50 mL) and H₂O (7 mL) in a 100-mL round-bottom flask under nitrogen was added cyclopropylboronic acid (0.49 g, 5.70 mmol). Then Pd(dppf)Cl₂ (278 mg, 0.38 mmol), SPhos (156 mg, 0.381 mmo) and Cs₂CO₃ (2.48 g, 7.62 mmol) were added. The resulting solution was stirred for 16 h at 80° C. under nitrogen. The insoluble was filtered out, the filter cake was washed with 200 mL of EtOAc. The filtrate was concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 946 mg (95.2%) of the title compound as a red solid. MS-ESI: 219 (M+1).

Step 4: 5-Bromo-6-cyclopropyl-4-nitro-2,3-dihydro-1H-indene

To a stirred solution of 6-cyclopropyl-4-nitro-2,3-dihydro-1H-inden-5-amine (946 mg, 4.33 mmol) in MeCN (50 mL) in a 100-mL round-bottom flask under nitrogen was added tert-butyl nitrite (670 mg, 6.50 mmol) dropwise at 0° C., CuBr (746 mg, 5.20 mmol) was added in portions at 0° C. The resulting solution was stirred for 3 h at 60° C. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel with EtOAc/PE (1:10). This resulted in 750 mg (61.3%) of the title compound as red oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.18 (s, 1H), 3.00-2.80 (m, 4H), 2.20-2.00 (m, 3H), 1.10-0.95 (m, 2H), 0.80-0.65 (m, 2H).

Step 5: 6-Cyclopropyl-5-methyl-4-nitro-2,3-dihydro-1H-indene

To a stirred solution of 5-bromo-6-cyclopropyl-4-nitro-2,3-dihydro-1H-indene (700 mg, 2.48 mmol) in toluene (42 mL) and H₂O (7 mL) in a 100-mL round-bottom flask under nitrogen was added 2,4,4,5,5-penta-methyl-1,3,2-dioxaborolane (528 mg, 3.72 mmol). Then Cs₂CO₃ (1.62 g, 4.96 mmol), Pd(dppf)Cl₂ (181 mg, 0.25 mmol) and SPhos (101 mg, 0.25 mmol) were added. The resulting solution was stirred for 16 h at 80° C. under nitrogen. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 265 mg (49.2%) of the title compound as dark yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.16 (s, 1H), 2.96-2.80 (m, 4H), 2.32 (s, 3H), 2.10-1.98 (m, 2H), 1.98-1.85 (m, 1H), 1.01-0.89 (m, 2H), 0.68-0.59 (m, 2H).

Step 6: 6-Cyclopropyl-5-methyl-2,3-dihydro-1H-inden-4-amine

To a stirred solution of 6-cyclopropyl-5-methyl-4-nitro-2,3-dihydro-1H-indene (265 mg, 1.22 mmol) in MeOH (25 mL) in a 100-mL round-bottom flask under nitrogen was added Pd/C (10% wt., 50 mg), the flask was evacuated and flushed with hydrogen 3 times. The resulting solution was stirred for 16 h at RT under hydrogen with a balloon. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 187 mg (81.9%) of the title compound as dark yellow oil. MS-ESI: 188 (M+1).

Intermediate 165

4-Amino-3,6,7,8-tetrahydro-as-indacen-1(2H)-one Step 1: 1-(2,3-Dihydro-1H-inden-4-yl)prop-2-en-1-ol

To a stirred solution of 2,3-dihydro-1H-indene-4-carbaldehyde (4.0 g, 27.4 mmol) in THF (50 mL) in a 100-mL round-bottom flask under nitrogen was added bromo(ethenyl)magnesium (27.4 mL, 27.4 mmol, 1.0 M in THF) dropwise at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 100 mL of water/ice. The resulting solution was extracted with 3×50 mL of DCM and the organic layers were combined then concentrated under vacuum. This resulted in 3.5 g (73.4%) of the title compound as brown oil. MS-ESI: 175 (M+1).

Step 1-(2,3-Dihydro-1H-inden-4-yl)prop-2-en-1-one

To a stirred solution of 1-(2,3-dihydro-1H-inden-4-yl)prop-2-en-1-ol (3.50 g, 20.1 mmol) in DCM (50 mL) in a 100-mL round-bottom flask under nitrogen was added Dess-Martin (8.52 g, 20.1 mmol) in portions at 0° C. The resulting solution was stirred for 1 h at RT. The resulting mixture was quenched by addition of sat. Na₂S₂O₃. The mixture was extracted with 3×200 mL EtOAc and the organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from a silica gel with EtOAc/PE (1:50 to 1:30). This resulted in 3 g (86.7%) of the title compound as a yellow solid. MS-ESI: 173 (M+1).

Step 3: 3,6,7,8-Tetrahydro-as-indacen-1(2H)-one

To a stirred solution of sulfuric acid (30 mL) in a 100-mL round-bottom flask under nitrogen was added a solution of 1-(2,3-dihydro-1H-inden-4-yl)prop-2-en-1-ol (3.0 g, 17.4 mmol) in DCM (5 mL) dropwise at 0° C. The resulting solution was stirred for 3 h at 50° C. in an oil bath. The resulting solution was poured into 200 mL of water/ice slowly. The resulting solution was extracted with 3×200 mL of DCM and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:30 to 1:10). This resulted in 1.0 g (33.3%) of the title compound as a yellow solid. MS-ESI: 173 (M+1).

Step 4: 4-Nitro-3,6,7,8-tetrahydro-as-indacen-1(2H)-one

To a stirred solution of sulfuric acid (5.00 mL) in a 100-mL round-bottom flask under nitrogen was added 3,6,7,8-tetrahydro-as-indacen-1(2H)-one (500 mg, 2.9 mmol) in portions at 0° C. To this was added nitric acid (365 mg, 5.8 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 1 h at 0° C. in a water/ice bath. The resulting solution was poured into 20 mL of water/ice slowly. The resulting solution was extracted with 3×20 mL of DCM concentrated under vacuum. This resulted in 400 mg (63%) of the title compound as a brown solid. MS-ESI: 218 (M+1).

Step 5: 4-Amino-3,6,7,8-tetrahydro-as-indacen-1(2H)-one

To a stirred solution of 4-nitro-3,6,7,8-tetrahydro-as-indacen-1(2H)-one (400 mg, 1.84 mmol) in MeOH (20 mL) in a 100-mL round-bottom flask under nitrogen was added Pd/C (10% wt., 100 mg), the flask was evacuated and flushed with hydrogen 3 times. The resulting solution was stirred for 16 h at RT under hydrogen with a balloon. The solids were collected by filtration. The resulting mixture was concentrated under vacuum. This resulted in 300 mg (87%) of the title compound as a brown solid. MS-ESI: 188 (M+1).

Intermediate 166

8-Allyl-1,2,3,5,6,7-hexahydro-s-indacen-4-amine Step 1: 8-Iodo-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

To a stirred solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (2.01 g, 12 mmol) in N,N-dimethylformamide (10 mL) in a 50-mL round-bottom flask was added NIS (2.97 g, 13.2 mmol). The resulting solution was stirred for 3 h at RT. The resulting solution was diluted with 100 mL of EtOAc. The resulting mixture was washed with 100 mL of brine. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:20). This resulted in 2.84 g (79%) of the title compound as an orange solid. MS-ESI: 300 (M+1).

Step 2: 8-Allyl-1,2,3,5,6,7-hexahydro-s-indacen-4-amine

To a stirred solution of 8-iodo-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (460 mg, 1.54 mmol) and PPh₃ (202 mg, 0.77 mmol) in DMF(15 mL) in 50 mL round-bottom flask under nitrogen was added Pd(pph₃)₂Cl₂ (216 mg, 0.31 mmol) and tributyl(prop-2-en-1-yl)stannane (432 mg, 1.3 mmol) at RT. The resulting mixture was stirred for 16 h at 120° C. under nitrogen. The resulting mixture was diluted with water (40 mL) and extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1:2) to afford the title compound (200 mg, 61%) as a brown solid. MS-ESI: 214 (M+1).

Intermediate 167

6-Isopropyl-2,3-dihydro-1H-inden-5-amine Step 1: 6-Bromo-2,3-dihydro-1H-inden-5-amine

To a stirred solution of 2,3-dihydro-1H-inden-5-amine (5 g, 37.5 mmol) in MeCN (300 mL) in a 500-mL round-bottom flask was added a solution of NBS (6.68 g, 37.5 mmol) in MeCN/THF (1:1, 40 mL) dropwise at 0° C. The resulting solution was stirred for 2 h at 0° C. in a water/ice bath. The reaction was then quenched by the addition of 100 mL of sat. NaHCO₃ (aq). The resulting solution was extracted with 3×100 mL of EtOAc and the organic phase was combined and dried over anhydrous Na₂SO₄, then concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:20). This resulted in 7.2 g (90%) of the title compound as purple oil. MS-ESI: 212 (M+1).

Step 2: 6-(Prop-1-en-2-yl)-2,3-dihydro-1H-inden-5-amine

To a stirred solution of 6-bromo-2,3-dihydro-1H-inden-5-amine (7.5 g, 35.4 mmol) in 1,4-dioxane (100 mL) and H₂O (10 mL) in a 250-mL round-bottom flask under nitrogen was added Cs₂CO₃ (23.1 g, 70.8 mmol). Then 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (8.9 g, 53.1 mmol) and Pd(dppf)Cl₂ (2.6 g, 3.54 mmol) were added. The resulting solution was stirred for 16 h at 80° C. The reaction was then quenched by the addition of 200 mL of water. The solids were filtered out. The resulting solution was extracted with 3×300 mL of EtOAc and the organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 5.8 g (94.8%) of the title compound as yellow oil. MS-ESI: 174 (M+1).

Step 3: 6-Isopropyl-2,3-dihydro-1H-inden-5-amine

To a stirred solution of 6-(prop-1-en-2-yl)-2,3-dihydro-1H-inden-5-amine (5.8 g, 33.5 mmol) in MeOH (100 mL) in a 250-mL round-bottom flask under nitrogen was added Pd/C (10% wt., 0.58 g). The flask was evacuated and flushed with hydrogen 3 times. The resulting solution was stirred for 16 h at RT under hydrogen with a balloon. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 5.77 g (98.3%) of the title compound as yellow oil. MS-ESI: 176 (M+1).

Intermediate 168

Tert-butyl (S)-(amino(3-fluoro-5-(2-hydroxypropan-2-yl)thiophen-2-yl)(oxo)-λ⁶-sulfaneylidene)carbamate Step 1: 2-(4-Fluorothiophen-2-yl)propan-2-ol

To a 250 mL 3-neck flask placed a solution of methyl 4-fluorothiophene-2-carboxylate (5.5 g, 34.3 mmol) in THF (55 mL) was added MeMgBr (1M in THF) (86 mL, 86 mmol) dropwise at 0° C. under nitrogen. The resulting solution was stirred for 3 h at 0° C. under nitrogen. LC showed reaction is completed. The resulting mixture was quenched with cold sat. aq. NH₄Cl (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×50 mL). The organic layer was dried over by anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was re-crystallized from PE/EtOAc (100:1) to afford (4.0 g, 72%) of the title compound as a light yellow solid. GCMS: 160 [M]. ¹H NMR (400 MHz, DMSO-d₆) δ 6.91 (d, J=1.7 Hz, 1H), 6.84 (d, J=1.7 Hz, 1H), 5.52 (s, 1H), 1.47 (s, 6H).

Step 2: (1S,2R)-1-((2,4,6-trimethylphenyl)sulfonamido)-2,3-dihydro-1H-inden-2-yl (S)-3-fluoro-5-(2-hydroxypropan-2-yl)thiophene-2-sulfinate

To a 100 mL 3-neck flask placed a solution of 2-(4-fluorothiophen-2-yl)propan-2-ol (2.0 g, 12.5 mmol) in THF (30 mL) was added LDA (2 M in hexane, 12.5 mL, 25 mmol) dropwise at −78° C. over 1 min under nitrogen. The resulting solution was stirred for 30 min at −78° C., this solution was assigned as A. The solution of (2R,3aS,8aR)-3-(mesitylsulfonyl)-3,3a,8,8a-tetrahydroindeno[1,2-d][1,2,3] oxathiazole 2-oxide (4.7 g, 12.5 mmol) in THF (10 mL) was transferred into the solution A, while the internal temperature of the resulting solution was kept below −65° C. under nitrogen. The resulting solution was stirred for 30 min at −70° C. under nitrogen. LC showed the reaction to be complete. The resulting mixture was quenched with cool sat. aq. NH₄Cl (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×50 mL). The organic layer was dried over by anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was re-crystallized from PE/EtOAc (10:1) to afford (2.6 g, 38%, de=100%) of the title compound as a white solid. MS-ESI: 560 [M+Na]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.19 (d, J=9.7 Hz, 1H), 7.27-7.17 (m, 2H), 7.18-7.12 (m, 1H), 7.04 (s, 2H), 7.01 (s, 1H), 6.92 (d, J=7.4 Hz, 1H), 5.86 (s, 1H), 4.98-4.89 (m, 1H), 4.80 (dd, J=9.6, 5.1 Hz, 1H), 3.22 (dd, J=16.7, 4.8 Hz, 1H), 3.08 (dd, J=16.7, 2.2 Hz, 1H), 2.61 (s, 6H), 2.28 (s, 3H), 1.49 (s, 3H), 1.48 (s, 3H).

Step 3: (S)-3-fluoro-5-(2-hydroxypropan-2-yl)thiophene-2-sulfinamide

The solution of (1S,2R)-1-((2,4,6-trimethylphenyl)sulfonamido)-2,3-dihydro-1H-inden-2-yl-(S)-3-fluoro-5-(2-hydroxypropan-2-yl)thiophene-2-sulfinate (1.5 g, 2.79 mmol) in THF (9 mL) was added in one portion to a stirred 50 mL of 3-neck flask placed a solution of NaHMDS (2M in THF) (5.6 ml, 11.2 mmol) in THF (15 mL) at −10° C. under nitrogen. The resulting solution was stirred for 1 h at −10° C. under nitrogen. LC showed the reaction to be complete. The resulting mixture was quenched with AcOH (704 mg, 11.7 mmol) and MeOH (1.5 mL) below 0° C. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×50 mL). The organic layer was dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was re-crystallized from PE/EtOAc (3:1) to afford (452 mg, 72%, ee=85.4%) of the title compound as a white solid. MS-ESI: 224 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 6.92 (s, 1H), 6.61 (s, 2H), 5.70 (s, 1H), 1.46 (s, 3H), 1.45 (s, 3H).

Step 4: Tert-butyl (S)-((3-fluoro-5-(2-hydroxypropan-2-yl)thiophen-2-yl)sulfinyl)carbamate

To a 25 mL 3-neck flask was added (S)-3-fluoro-5-(2-hydroxypropan-2-yl)thiophene-2-sulfinamide (200 mg, 0.62 mmol, ee=85.4%), this was followed by the addition of 3.0 mL of dry THF under nitrogen. The reaction mixture was cooled to 0° C. and KOtBu (120 mg, 0.74 mmol) was added (internal temperature was controlled below 0° C.). The solution was stirred for 30 min then the Boc₂O (195 mg, 0.62 mmol) in 1.0 mL of THF was added. The ice bath was removed and the reaction mixture was stirred at RT for 1 h. LC showed the reaction to be complete. The resulting mixture was quenched with aq. NH₄Cl (25 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (2×5 mL). The organic layer was dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was re-crystallized from PE/EtOAc (5:1) to afford (49 mg, 17%, ee=97.4%) of the title compound as a white solid. MS-ESI: 386 [M+Na+MeCN]⁺, ¹H NMR (300 MHz, DMSO-d₆) δ 10.96 (s, 1H), 7.03 (s, 1H), 5.85 (s, 1H), 1.50 (s, 3H), 1.48 (s, 3H), 1.46 (s, 9H).

Step 5: Tert-butyl (S)-(amino(3-fluoro-5-(2-hydroxypropan-2-yl)thiophen-2-yl)(oxo)-λ⁶-sulfaneylidene) carbamate

To a 10 mL 3-neck flask was added tert-butyl (S)-((3-fluoro-5-(2-hydroxypropan-2-yl)thiophen-2-yl) sulfinyl)carbamate (15 mg, 0.046 mmol, ee=97.4%), this was followed by the addition of dry THF (0.3 mL) under nitrogen. The reaction mixture was cooled to 0° C. and TCCA (3.8 mg, 0.016 mmol) was added portion-wise to avoid any exotherm and extensive over-chlorination. The reaction was stirred at 0° C. for 1 h. This solution was assigned as A. The solution A was cooled to −50° C. and the solution of NH₃ (7 M in MeOH) was added dropwise via syringe. The reaction was stirred at −50° C. for 1 h. LC showed the reaction to be complete. After filtration, the filtrate was purified by Prep-HPLC to afford (3.0 mg, 19% , ee=97.9%) of the title compound as a white solid. MS-ESI: 339 (M+1). ¹H NMR (400 MHz, MeOH-d₄) δ 6.81 (s, 1H), 1.58 (s, 6H), 1.39 (s, 9H).

Intermediate 169

6-Cyclopropyl-4-isocyanato-5-methyl-2,3-dihydro-1H-indene

To a stirred solution of 6-cyclopropyl-5-methyl-2,3-dihydro-1H-inden-4-amine (187 mg, 1.0 mmol) in THF (30 mL) in a 100-mL round-bottom flask under nitrogen was added TEA (101 mg, 1.0 mmol) and triphosgene (148 mg, 0.5.0 mmol). The resulting solution was stirred for 2 h at 70° C. in an oil bath. The resulting mixture was concentrated under vacuum. This resulted in 213 mg (crude) of the title compound as yellow oil. This was used in the next step without further purification.

TABLE 34 The Intermediates in the following Table were prepared using the similar procedures for converting Intermediate 164 to Intermediate 169 shown in Scheme 121. Intermediate # Structure IUPAC Name Intermediate 170

4-Isocyanato-3,6,7,8-tetrahydro-as-indacen-1(2H)-one Intermediate 171

4-Allyl-8-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene Intermediate 172

5-Isocyanato-6-isopropyl-2,3-dihydro-1H-indene

Intermediate 173

2,2,2-Trichloroethyl (8-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamate

To a stirred solution of 8-amino-1,2,3,5,6,7-hexahydro-s-indacene-4-carbonitrile (700 mg, 3.54 mmol) in THF (10 mL) in a 100-mL round-bottom flask was added DIEA (912 mg, 7.07 mmol) and 2,2,2-trichloroethyl chloroformate (1.49 g, 7.07 mmol). The resulting solution was stirred for 12 h at RT. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3×30 mL of EtOAc and the organic layers combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 1.1 g (83.3%) of the title compound as yellow solid. MS-ESI: 373/375/377 (M+1).

TABLE 34 The Intermediates in the following Table were prepared using the similar procedures for converting Intermediate 40 to Intermediate 173 shown in Scheme 122. Exact Mass Intermediate # Structure IUPAC Name [M + H]⁺ Intermediate 174

2,2,2-Trichloroethyl (3-oxo-1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamate 362/354/ 367 Intermediate 175

2,2,2-Trichloroethyl (1-oxo-1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamate 362/364/ 367

Intermediate 176

Tert-butyl ((5-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)thiophen-3-yl)methyl)(methyl)carbamate

Steps 1-2 used similar procedures for converting compound 431″ to compound 433″ shown in Scheme 91 to afford compound 615″ from compound 613″. MS-ESI: 219 (M−1).

Steps 3-6 used similar procedures for converting compound 242 to compound 470″ shown in Scheme 97 to afford intermediate 619″ from compound 615″. MS-ESI: 307 (M+1).

Steps 7-9 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford intermediate 176 from compound 619″. MS-ESI: 420 (M+1).

Intermediate 177

N′-(tert-butyldimethylsilyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-2-sulfonimidamide Step 1: 6,7-Dihydro-4H-thieno[3,2-c]pyran

To a stirred solution of 2-(thiophen-2-yl)ethan-1-ol (10 g, 78 mmol) in ACN (400 mL) in a 1-L round-bottom flask under nitrogen was added paraformaldehyde (3.02 g, 34 mmol) at RT, followed by the addition of InCl₃ (863 mg, 3.9 mmol) in portions at 0° C. The resulting solution was stirred for 2 h at 70° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:10). This resulted in 6.0 g (55%) of the title compound as brown oil. MS-ESI: 141 (M+1).

Step 2: 6,7-Dihydro-4H-thieno[3,2-c]pyran-2-sulfonyl chloride

To a stirred solution of 6,7-dihydro-4H-thieno[3,2-c]pyran (2.0 g, 14 mmol) in DCE (100 mL) under nitrogen was added N,N-dimethylformamide sulfur trioxide complex (SO₃-DMF complex) (2.62 g, 17 mmol) dropwise at RT. The resulting solution was stirred for 1 h at RT. Then to the stirred solution was added SOCl₂ (2.04 g, 17 mmol) dropwise at 0° C. The resulting solution was stirred for 4 h at 50° C. The reaction solution was quenched with ice/water (20 mL). The resulting mixture was extracted with EtOAc (4×100 mL). The organic layers were combined and concentrated under vacuum. This resulted in 2.1 g (crude) of the title compound as a yellow solid.

Step 3: 6,7-Dihydro-4H-thieno[3,2-c]pyran-2-sulfonamide

To stirred solution of 6,7-dihydro-4H-thieno[3,2-c]pyran-2-sulfonyl chloride (2.1 g, crude from last step) in DCM (100 mL) was introduced NH₃ gas bubbled for 15 min at 0° C. The resulting solution was stirred overnight at RT. The reaction solution was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 800 mg (25.6% over two steps) of the title compound as a yellow solid. MS-ESI: 218 (M−1).

Steps 4-5 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford intermediate 177 from compound 625″. MS-ESI: 333 (M+1).

Intermediate 178

2-((R)-1-azido-2-hydroxypropan-2-yl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiazole-5-sulfonimidamide Step 1: (R) and (S)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonamide

Compound 586″ (10 g) was resolved by Prep-Chiral-HPLC with the following conditions: CHIRALPAK AD, 5*25 cm, 5 um; Mobile Phase A: CO₂, Mobile Phase B: MeOH(2 mM NH₃-MeOH); Flow rate: 200 mL/min; Gradient:40% B; 220 nm; Rt₁: 3.5 (Compound 586″A); Rt₂: 5.6 (Compound 586″B). This resulted in 4.1 g (99% ee) of Compound 586″A and 4.0 g (98% ee) of Compound 586″B both as a white solid. MS-ESI: 237 (M−1).

Step 2: (R)-2-hydroxy-2-(5-sulfamoylthiazol-2-yl)propyl 4-methylbenzenesulfonate

To a stirred solution of (R)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonamide (4.0 g, 17 mmol) in pyridine (40 mL) in a 250-mL round-bottom flask under nitrogen was added 4-methylbenzenesulfonyl chloride (4.8 g, 25 mmol) in portions at 0° C. The resulting solution was stirred overnight at RT. The resulting mixture was quenched with HCl (1 M, 40 mL). The resulting mixture was extracted with 3×40 mL ethyl acetate. The combined organic layer was dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in 5.2 g (79%) of the title compound as a yellow solid. MS-ESI: 391 (M−1).

Step 3: (R)-2-(1-azido-2-hydroxypropan-2-yl)thiazole-5-sulfonamide

To a stirred solution of (R)-2-hydroxy-2-(5-sulfamoylthiazol-2-yl)propyl 4-methylbenzenesulfonate (3.2 g, 8.2 mmol) in EtOH (40 mL) in a 250-mL round-bottom flask under nitrogen was added NH₄Cl (2.18 g, 41 mmol) at RT, followed by the addition of NaN₃(1.3 g, 20 mmol) in portions at 0° C. carefully. The resulting solution was stirred overnight at 80° C. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with 3×30 mL ethyl acetate. The combined organic layer was dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in 2.1 g (98%) of the title compound as a yellow solid. MS-ESI: 264 (M+1).

Steps 4-5 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford compound 630″ from compound 628″. MS-ESI: 377 (M+1).

Step 6: 2-((R)-1-azido-2-hydroxypropan-2-yl)-N-(tert-butyldimethylsilyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiazole-5-sulfonimidamide

To a stirred solution of 2-((R)-1-azido-2-hydroxypropan-2-yl)-N′-(tert-butyldimethylsilyl)thiazole-5-sulfonimidamide (1.7 g, 4.5 mmol) in THF (10 mL) in a 100-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 540 mg, 13.5 mmol) in portions at 0° C. The resulting solution was stirred for 5 min at 0° C. To the above solution was added 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (900 mg, 4.5 mmol) in small portions at 0° C. The resulting mixture was stirred for 1 h at RT. The reaction was quenched with water/ice (10 mL) at 0° C. The resulting mixture was extracted with ethyl acetate (3×15 mL). The combined organic layer was dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3.0 g (crude) of the title compound as yellow oil. MS-ESI: 576 (M+1).

Step 7: 2-((R)-1-azido-2-hydroxypropan-2-yl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) thiazole-5-sulfonimidamide

To a stirred solution of 2-((R)-1-azido-2-hydroxypropan-2-yl)-N-(tert-butyldimethylsilyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiazole-5-sulfonimidamide (3.0 g, crude) in THF (20 mL) in a 100-mL round-bottom flask was added HF-pyridine (2.0 mL) dropwise at ° C. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 1.6 g (76.8% over two steps) of the title compound as a yellow solid. MS-ESI: 462 (M+1).

Intermediate 179

2-((R)-1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)-N-(tert-butyldimethylsilyl)thiazole-5-sulfonimidamide Step 1: (R)-2-(1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonamide

To a stirred solution of 2-(benzyloxy)ethan-1-ol (3.88 g, 25.5 mmol) in THF (30 mL) in a 100-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 2.04 g, 51 mmol) in portions at 0° C. The resulting mixture was stirred for 30 min at 0° C. (R)-2-hydroxy-2-(5-sulfamoyl-thiazol-2-yl)propyl 4-methylbenzenesulfonate (2.0 g, 5.1 mmol) in THF (10 mL) was added to the solution dropwise at 0° C. The resulting solution was stirred for 32 h at 35° C. The reaction was quenched with ice/water (100 mL) at 0° C. The resulting mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (2×200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (1:2). This resulted in 1.8 g (95%) of the title compound as a yellow solid. MS-ESI: 371 (M−1).

Steps 2-4 used similar procedures for converting compound 362″ to intermediate 124 shown in Scheme 80 to afford intermediate 179″ from compound 632″. MS-ESI: 486 (M+1).

TABLE 35 The Intermediate 180 was prepared using similar procedures for converting compound 627″ to Intermediate 179 shown in Scheme 126 from appropriate starting materials. Exact Intermediate Mass # Structure IUPAC Name [M + H]⁺ Intermediate 180

N-(tert-butyldimethylsilyl)-2-((R)-2-hydroxy-1-(2- methoxyethoxy)propan-2-yl)thiazole-5-sulfonimidamide 410

Intermediate 181

N-(tert-butyldimethylsilyl)-3-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)-N-methylbenzenesulfonamide Step 1: N₁,N₃-bis(tert-butyldimethylsilyl)-N1-methylbenzene-1,3-disulfonamide

To a stirred solution of N-methylbenzene-1,3-disulfonamide (220 mg, 0.88 mmol) in THF (6 mL) in a 25-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 211 mg, 5.28 mmol) in portions at 0° C. The resulting solution was stirred for 20 min at RT. To the solution was added TBSCl (397 mg, 2.64 mmol) in portions at 0° C. The resulting solution was stirred overnight at RT. The reaction solution was quenched with 10 mL water. The mixture was extracted with 3×20 mL ethyl acetate. The organic layer was dried with anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:2). This resulted in 400 mg (95%) of the title compound as yellow oil. MS-ESI: 479 (M+1).

Steps 2-4 used similar procedures for converting compound 363″ to intermediate 124 shown in Scheme 80 to afford intermediate 181 from compound 636″. MS-ESI: 478 (M+1).

TABLE 36 The Intermediate 146 was prepared using similar procedures for converting compound 459″ to Intermediate 139 shown in Scheme 95 from appropriate starting materials. Exact Intermediate Mass # Structure IUPAC Name [M + H]⁺ Intermediate 182

N′-(tert-butyldimethylsilyl)-5-methyl-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-sulfonimidamide 346

Scheme for the preparation of Key Intermediates: Schemes below illustrate the preparation of key intermediates.

Intermediate 183

Tert-butyl 2-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate Step 1: Tert-butyl 2-sulfamoyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate

To a stirred solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-sulfonamide hydrochloride (1.0 g, 4.58 mmol, an intermediate to Intermediate 182) in THF (20 mL) in a 100-mL round-bottom flask were added TEA (1.39 g, 13.7 mmol) at RT, followed by the addition of Boc₂O (1.0 g, 4.58 mmol) in portions at RT. The reaction mixture was stirred for 2 h at RT and then was concentrated under vacuum. The residue was eluted from silica gel with EtOAc (100%). This resulted in 1.0 g (69%) of the title compound as a light yellow solid. MS-ESI: 319 (M+1).

Step 2: Tert-butyl 2-(N-(tert-butyldimethylsilyl)sulfamoyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate

To a stirred solution of tert-butyl 2-sulfamoyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (500 mg, 1.57 mmol) in THF (15 mL) in a 100-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 126 mg, 3.14 mmol) in portions at 0° C. The resulting mixture was stirred for 10 min at RT, followed by the addition of TBSCl (473 mg, 3.14 mmol) in portions at 0° C. The reaction mixture was stirred for 2 h at RT. The reaction was quenched with water (10 mL) at 0° C. The mixture was extracted with EtOAc (3×20 mL) and the organic layers were combined. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. This resulted in 723 mg (crude) of the title compound as light yellow liquid. MS-ESI: 433 (M+1).

Step 3: Tert-butyl 2-(N-(tert-butyldimethylsilyl)sulfamidimidoyl)-6,7-dihydrothieno[3,2-c]pyridine-5 (4H)-carboxylate

To a stirred mixture of PPh₃Cl₂ (693 mg, 2.08 mmol) in CHCl₃ (10 mL) a 100-mL 3-necked round-bottom flask under nitrogen was added DIEA (537 mg, 4.16 mmol) dropwise at 0° C. The reaction mixture was stirred for 15 min at 0° C. To the above mixture was added tert-butyl 2-(N-(tert-butyldimethylsilyl)sulfamoyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (723 mg, crude) in CHCl₃ (5.0 mL) dropwise over 5 min at 0° C. The reaction mixture was stirred for additional 30 min at 0° C. NH₃ (gas) was bubbled into the above mixture for 15 min at 0° C. The reaction mixture was stirred overnight at RT. The reaction mixture was filtered, the filter cake was washed with DCM (10 mL). The filtrate and wash were combined and concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc (100%). This resulted in 300 mg (44%, over two steps) of the title compound as a light yellow solid. MS-ESI: 432 (M+1).

Intermediate 184

N′-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazole-5-sulfonimidamide Step 1: 2-Bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole

To a stirred solution of (2-bromothiazol-4-yl)methanol (13 g, 67 mmol) in THF (150 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 8.0 g, 201 mmol) in portions at 0° C. in an ice/water bath. The reaction mixture was stirred for 10 min at RT. Then to the above mixture was added TBSCl (30.3 g, 201 mmol) in portions at 0° C. The reaction mixture was stirred for 2 h at RT. The reaction was quenched with 200 mL of water. The mixture was extracted with 3×300 mL of EtOAc and the organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:30). This resulted in 15 g (73%) of the title compound as yellow oil. MS-ESI: 308/310 (M+1).

Step 2: 5-(4-(((Tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-2,2-dimethyl-1,3-dioxan-5-ol

To a stirred solution of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole (1.4 g, 4.55 mmol) in THF (30 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 1.8 mL, 4.55 mmol) dropwise at −78° C. The reaction solution was stirred for 30 min at −78° C. Then to the solution was added 2,2-dimethyl-1,3-dioxan-5-one (621 mg, 4.78 mmol) in THF (5 mL) dropwise at −78° C. The reaction mixture was stirred for 1 h at −78° C. The reaction was quenched with H₂O (20 mL) at 0° C. The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by prep-TLC (PE/EtOAc 10:1). This resulted in 1.1 g (67%) of the title compound as brown oil. MS-ESI: 360 (M+1).

Step 3: 4-(((Tert-butyldimethylsilyl)oxy)methyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazole-5-sulfinic acid, lithium salt

To a stirred solution of 5-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-2,2-dimethyl-1,3-dioxan-5-ol (1.1 g, 3.06 mmol) in THF (30 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 2.7 mL, 6.73 mmol) dropwise at −78° C. The reaction solution was stirred for 30 min at −78° C. Then SO₂ (g) was bubbled to the solution at −50° C. for 20 min. The reaction mixture was allowed to react with stirring for an additional 2 h at RT. The mixture was concentrated directly under vacuum. This resulted in 1.5 g (crude) of the title compound as a yellow solid. MS-ESI: 422 (M−1).

Step 4: 4-(((Tert-butyldimethylsilyl)oxy)methyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazole-5-sulfonyl chloride

To a stirred solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl) thiazole-5-sulfinic acid, lithium salt (1.5 g, crude) in THF (20 mL) in a 100-mL round-bottom flask was added NCS (610 mg, 4.59 mmol) in portions at 0° C. The reaction mixture was stirred for 2 h at 0° C. To the reaction solution was added NH₃ in THF (0.5 M, 50 mL) in portions at 0° C. The reaction mixture was stirred for 2 h at 0° C. The mixture was concentrated under vacuum. The residue was purified by prep-TLC (PE/EtOAc 7:1). This resulted in 685 mg (51%, over two steps) of the title compound as a brown solid. MS-ESI: 439 (M+1).

Steps 5-6 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 184 from compound 644″. MS-ESI: 552 (M+1).

Intermediate 185

5-(Azetidin-1-ylmethyl)-N′-(tert-butyldimethylsilyl)-3-fluorothiophene-2-sulfonimidamide Step 1: 1-((4-Fluorothiophen-2-yl)methyl)azetidine

To a stirred solution of 2-(bromomethyl)-4-fluorothiophene (2.4 g, 12.4 mmol) in THF (25 mL) in a 100-mL round-bottom flask under nitrogen were added azetidine (1.06 g, 18.6 mmol) and TEA (2.49 g, 25 mmol) in portions at RT. The reaction solution was stirred for 2 h at RT. The reaction solution was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 2.0 g (94%) of the title compound as yellow oil. MS-ESI: 172 (M+1).

Steps 2-4 used similar procedures for converting compound 642″ to Intermediate 184 shown in Scheme 129 to afford Intermediate 185 from compound 646″. MS-ESI: 364 (M+1).

Intermediate 186

Tert-butyl ((5-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)-4-fluorothiophen-2-yl)methyl)(cyclobutyl)carbamate Step 1: N-((4-fluorothiophen-2-yl)methyl)cyclobutanamine

To a stirred solution of 2-(bromomethyl)-4-fluorothiophene (4.5 g, 23 mmol) in EtOH (100 mL) in a 250-mL round-bottom flask under nitrogen were added cyclobutanamine (2.0 g, 28 mmol) at 0° C., followed by the addition of NaOH (1.5 g, 38 mmol) in portions at 0° C. The reaction mixture was stirred overnight at RT. The reaction mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 3.5 g (82%) of the title compound as a yellow solid. MS-ESI: 186 (M+1).

Step 2: Tert-butyl cyclobutyl((4-fluorothiophen-2-yl)methyl)carbamate

To stirred solution of N-((4-fluorothiophen-2-yl)methyl)cyclobutanamine (3.5 g, 19 mmol) in DCM (50 mL) in a 250-mL round-bottom flask under nitrogen were added Et₃N (5.4 mL, 38 mmol) at RT, followed by the addition of Boc₂O (5.0 g, 23 mmol) at RT. The reaction mixture was stirred for 3 h at RT. The reaction was quenched with 100 mL of water. The mixture was extracted with 3×100 mL of DCM and the organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (5:1). This resulted in 4.6 g (85%) of the title compound as a yellow solid. MS-ESI: 286 (M+1).

Steps 3-6 used similar procedures for converting compound 642″ to Intermediate 184 shown in Scheme 129 to afford Intermediate 186 from compound 650″. MS-ESI: 478 (M+1).

Intermediate 187

Tert-butyl ((5-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)thiophen-2-yl)(cyclopropyl)methyl)(methyl)carbamate Step 1: 5-Bromo-N-(tert-butyl)thiophene-2-sulfonamide

To a stirred solution of 5-bromothiophene-2-sulfonyl chloride (20 g, 77 mmol) in DCM (200 mL) in a 1-L round-bottom flask were added 2-methylpropan-2-amine (8.43 g, 116 mmol) at RT, followed by the addition of TEA (15.6 g, 154 mmol) at RT. The reaction mixture was stirred overnight at RT and then was quenched with 10 mL of water. The mixture was extracted with 3×150 mL of DCM and the organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. This resulted in 20.1 g (88%) of the title compound as a red solid. MS-ESI: 298/300 (M+1).

Step 2: N-(tert-butyl)-5-(cyclopropanecarbonyl)thiophene-2-sulfonamide

To a stirred solution of 5-bromo-N-(tert-butyl)thiophene-2-sulfonamide (20 g, 67 mmol) in THF (500 mL) in a 1-L 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 67 mL, 168 mmol) dropwise at −78° C. The reaction solution was stirred for 1 h at −78° C. To the reaction solution was added N-methoxy-N-methylcyclopropanecarboxamide (35 g, 270 mmol) in THF (20 mL) dropwise at −78° C. Then the reaction mixture was stirred for 1 h at −78° C. The reaction was quenched with 20 mL of MeOH. The mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (21%). This resulted in 7.1 g (37%) of the title compound as a white solid. MS-ESI: 288 (M+1).

Step 3: N-(tert-butyl)-5-(cyclopropyl(hydroxy)methyl)thiophene-2-sulfonamide

To a stirred solution of N-(tert-butyl)-5-(cyclopropanecarbonyl)thiophene-2-sulfonamide (2.0 g, 6.96 mmol) in MeOH (40 mL) in a 100-mL round-bottom flask under nitrogen was added NaBH₄ (529 mg, 14 mmol) at 0° C. The reaction mixture was stirred for 2 h at RT. The reaction was quenched with 10 mL of water. The mixture was extracted with 3×100 mL of EtOAc and the organic layers were combined. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. This resulted in 1.8 g (89%) of the title compound as yellow oil. MS-ESI: 290 (M+1).

Step 4: N-(tert-butyl)-5-(cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)thiophene-2-sulfonamide

To a stirred solution of N-(tert-butyl)-5-(cyclopropyl(hydroxy)methyl)thiophene-2-sulfonamide (1.2 g, 4.15 mmol) in THF (24 mL) in a 100-mL round-bottom flask under nitrogen were added isoindoline-1,3-dione (610 mg, 4.15 mmol) and PPh₃ (1.63 g, 6.22 mmol) at RT. To the stirred mixture was added DIAD (1.26 g, 6.22 mmol) dropwise at 0° C. The reaction mixture was stirred overnight at RT. The mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:6). This resulted in 1.7 g (98%) of the title compound as a yellow solid. MS-ESI: 419 (M+1).

Step 5: 5-(Amino(cyclopropyl)methyl)-N-(tert-butyl)thiophene-2-sulfonamide

To a stirred solution of N-(tert-butyl)-5-(cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl)thiophene-2-sulfonamide (200 mg, 0.48 mmol) in EtOH (10 mL) in a 50-mL round-bottom flask was added NH₂NH₂.H₂O (80% wt., 180 mg, 2.88 mmol). The reaction solution was stirred for 3 h at 80° C. The reaction solution was concentrated under vacuum. The residue was dissolved in 10 mL of DCM. The solids were filtered out and the filtrate was concentrated under vacuum. This resulted in 100 mg (73%) of the title compound as yellow oil. MS-ESI: 289 (M+1).

Step 6: Tert-butyl ((5-(N-(tert-butyl)sulfamoyl)thiophen-2-yl)(cyclopropyl)methyl)carbamate

To a stirred solution of 5-(amino(cyclopropyl)methyl)-N-(tert-butyl)thiophene-2-sulfonamide (100 mg, 0.35 mmol) in DCM (10 mL) in a 50-mL round-bottom flask were added TEA (70 mg, 0.69 mmol) at RT, followed by the addition of Boc₂O (151 mg, 0.69 mmol) at RT. The reaction solution was stirred overnight at 40° C. The reaction solution was diluted with H₂O (10 mL). The mixture was extracted with 3×20 mL of DCM and the organic layers were combined. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1/3). This resulted in 100 mg (74%) of the title compound as yellow oil. MS-ESI: 389 (M+1).

Step 7: N-(tert-butyl)-5-(cyclopropyl(methylamino)methyl)thiophene-2-sulfonamide

To a stirred solution of tert-butyl ((5-(N-(tert-butyl)sulfamoyl)thiophen-2-yl)(cyclopropyl)methyl)carbamate (100 mg, 0.26 mmol) in THF (10 mL) in a 50-mL round-bottom flask under nitrogen was added LiAlH₄ (30 mg, 0.78 mmol) at 0° C. The reaction mixture was stirred for 2 h at 80° C. The reaction was quenched with 5.0 mL of water. The reaction mixture was concentrated under vacuum. The residue was dissolved in 10 mL of MeOH. The solids were filtered and the filtrate was concentrated under vacuum. This resulted in 74 mg (94%) of the title compound as off-white oil. MS-ESI: 303 (M+1).

Step 8: 5-(Cyclopropyl(methylamino)methyl)thiophene-2-sulfonamide

A solution of N-(tert-butyl)-5-(cyclopropyl(methylamino)methyl)thiophene-2-sulfonamide (74 mg, 0.24 mmol) in HCl in 1,4-dioxane (4 M, 5.0 mL, 2.0 mmol) in a 50-mL round-bottom flask was stirred overnight at RT. The reaction mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 53 mg (89%) of the title compound as yellow oil. MS-ESI: 247 (M+1).

Step 9: Tert-butyl (cyclopropyl(5-sulfamoylthiophen-2-yl)methyl)(methyl)carbamate

To a stirred solution of 5-(cyclopropyl(methylamino)methyl)thiophene-2-sulfonamide (53 mg, 0.21 mmol) in DCM (8 mL) in a 25-mL round-bottom flask was added TEA (43 mg, 0.43 mmol) at RT, followed by the addition of Boc₂O (69 mg, 0.32 mmol) at RT. The reaction solution was stirred overnight at 40° C. The reaction was diluted with H₂O (8 mL). The mixture was extracted with 3×8 mL of DCM and the organic layers combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1/3). This resulted in 51 mg (70%) of the title compound as yellow oil. MS-ESI: 347 (M+1).

Steps 10-11 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 187 from compound 663″. MS-ESI: 460 (M+1).

Step 12: Tert-butyl (S) and (R)-(cyclopropyl(5-sulfamoylthiophen-2-yl)methyl)(methyl)carbamate

Tert-butyl (cyclopropyl(5-sulfamoylthiophen-2-yl)methyl)(methyl)carbamate (663″, 1.0 g) was resolved by Chiral-Prep-HPLC using the following conditions: Column CHIRALPAK IG, 2*25 cm, 5 um; Mobile Phase A: Hex (8 mM NH₃ ⁻MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 20 B to 20 B over 17 min; UV 254/220 nm; Rt₁: 8.479 (663″F); Rt₂: 10.122 (663″S); Injection Volumn:0.5 ml; Number of runs:39. This resulted in 417 mg (98% ee) of 663″F and 407 mg (99% ee) of 663″S both as yellow solid. MS-ESI: 347 (M+1). The stereochemistry of 663″F and 663″S were assigned arbitrarily for registration purpose.

TABLE 54 The Intermediates in the following table were prepared using the similar procedures for converting compound 633″ to Intermediate 187 shown in Scheme 132 starting from 663″F or 663″S. Intermediate Exact Mass # Structure IUPAC Name [M − H]⁻ Intermediate 187F

Tert-butyl ((1S) or (1R)-(5-(N′-(tert- butyldimethylsilyl)sulfamidimidoyl)thiophen-2- yl)(cyclopropyl)methyl)(methyl)carbamate 460 Intermediate 187S

Tert-butyl ((1R) or (1S)-(5-(N′-(tert- butyldimethylsilyl)sulfamidimidoyl)thiophen-2- yl)(cyclopropyl)methyl)(methyl)carbamate 460

Intermediate 188

Step 1: 1-((Tert-butyldimethylsilyl)oxy)-2-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)propan-2-ol

-   -   To a stirred solution of         2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole (300         mg, 0.97 mmol) in THF (10 mL) in a 50-mL 3-necked round-bottom         flask under nitrogen was added n-BuLi in hexane (2.5 M, 0.4 mL,         0.97 mmol) dropwise at −78° C. The reaction solution was stirred         for 30 min at −78° C. To the solution was added         1-((tert-butyldimethylsilyl)oxy)propan-2-one (183 mg, 0.97 mmol)         at −78° C. over 10 min. The reaction mixture was stirred for 12         h at RT. The reaction was quenched with 10 mL of H₂O (10 mL).         The mixture was extracted with 3×20 mL of DCM and the organic         layers were combined and concentrated under vacuum. The residue         was eluted from silica gel with EtOAc/PE (1:10). This resulted         in 250 mg (62%) of the title compound as yellow oil. MS-ESI: 418         (M+1).

Steps 2-6 used similar procedures for converting compound 642″ to Intermediate 184 shown in Scheme 129 to afford Intermediate 188 from compound 665″. MS-ESI: 610 (M+1).

Step 7: (S) and (R)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole-5-sulfonamide

2-(1-((Tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole-5-sulfonamide (668″, 1.0 g) was resolved by Prep-SFC using the following conditions: Column: Lux Cellulose-4, 5*25 cm, 5 um; Mobile Phase A: CO₂, Mobile Phase B: MeOH; Flow rate: 150 mL/min; Gradient: 25% B; 220 nm; Rt₁: 3.81 min. (668″A); Rt₂: 4.88 min. (668″B); Injection Volume: 1.5 ml; number of runs: 40. This resulted in 420 mg (98% ee) of 668″A and 428 mg (99% ee) of 668″B both as yellow solid. MS-ESI: 497 (M+1).

TABLE 55 The intermediates in the following table were prepared using the similar procedures for converting compound 668″ to Intermediate 188 shown in Scheme 133 starting from 668″A or 668″B. Exact Intermediate Mass # Structure IUPAC Name [M − H]⁻ Intermediate 188A

(R) or (S) N′-(tert-butyldimethylsilyl)-2-(1-((tert- butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-4-(((tert- butyldimethylsilyl)oxy)methyl)thiazole-5-sulfonimidamide 610 Intermediate 188B

(S) or (R) N′-(tert-butyldimethylsilyl)-2-(1-((tert- butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-4-(((tert- butyldimethylsilyl)oxy)methyl)thiazole-5-sulfonimidamide 610

Intermediate 189F

N′-tert-butyldimethylsilyl)-5-methoxy-4,5,6,7-tetrahydrobenzo[c]thiophene-1-sulfonimidamide Step 1: 4,5,6,7-Tetrahydrobenzo[c]thiophen-5-ol

To a stirred solution of 6,7-dihydrobenzo[c]thiophen-5(4H)-one (3.7 g, 24 mmol) in MeOH (100 mL) in a 250-mL round-bottom flask under nitrogen was added NaBH₄ (1.09 g, 29 mmol) in portions at 0° C. The resulting mixture was stirred for 5 h at RT. The reaction was quenched with H₂O (5.0 mL). The mixture was extracted with 3×50 mL of DCM and the organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:40). This resulted in 3.0 g (80%) of the title compound as yellow oil. MS-ESI: 155 (M+1).

Step 2: 5-Methoxy-4,5,6,7-tetrahydrobenzo[c]thiophene

To a stirred solution of 4,5,6,7-tetrahydrobenzo[c]thiophen-5-ol (3.0 g, 19.5 mmol) in THF (30 mL) in a 100-mL round-bottom flask was added NaH (60% wt. dispersion in mineral oil, 1.95 g, 49 mmol) at 0° C. The reaction mixture was stirred for 10 min at RT, followed by the addition of CH₃I (4.15 g, 29.2 mmol) dropwise at RT. The reaction mixture was stirred for 5 h at RT. The reaction was then quenched with H₂O (30 mL). The mixture was extracted with 3×50 mL of DCM and the organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:80). This resulted in 3.0 g (91%) of the title compound as yellow oil. MS-ESI: 169 (M+1).

Step 3: 5-Methoxy-4,5,6,7-tetrahydrobenzo[c]thiophene-1-sulfonyl chloride and its Regioiosmer

To a stirred solution of 5-methoxy-4,5,6,7-tetrahydrobenzo[c]thiophene (3.0 g, 18 mmol) in CHCl₃ (30 mL) in a 100-mL 3-necked round-bottom flask was added ClSO₃H (2.49 g, 21 mmol) dropwise at −10° C. The reaction mixture was stirred for 48 h at RT. Then to the above mixture was added PCl₅ (7.36 g, 35.7 mmol) at −10° C. The reaction mixture was stirred for 3 h at 50° C. and then poured into 200 mL of water/ice. The mixture was extracted with 3×200 mL of DCM. The organic layers were combined, dried over anhydrous Na₂SO₄, and then concentrated under vacuum. This resulted in 1.5 g (crude) of the title compound as light brown oil. This crude product was used in the next step.

Step 4: 5-Methoxy-4,5,6,7-tetrahydrobenzo[c]thiophene-1-sulfonamide and 6-methoxy-4,5,6,7-tetrahydrobenzo[c]thiophene-1-sulfonamide and its Regio-isomer

To a stirred solution of 5-methoxy-4,5,6,7-tetrahydrobenzo[c]thiophene-1-sulfonyl chloride from Step 3 above (1.5 g, crude) in DCM (50 mL) in a 250-mL round-bottom flask was bubbled NH₃ (g) for 15 min at 0° C. The reaction mixture was stirred for 3 h at RT and concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:4 to 1:2). This resulted in 650 mg (15% over two steps) of 674″F and 620 mg (14%) of 674″S, both as a yellow solid. MS-ESI: 248 (M+1). The regiochemistry of 674″F and 674″S were assigned based on NMR including COSY and NOESY.

Compound 674″F: ¹H NMR (300 MHz, DMSO-d₆) δ 7.46 (br s, 2H), 7.34 (s, 1H), 3.75-3.55 (m, 1H), 3.26 (s, 3H), 2.99-2.80 (m, 3H), 2.71 (dd, J=16.3, 5.9 Hz, 1H), 1.95-1.75 (m, 2H).

NOESY: Ar—H 7.34 (s, 1H) correlated with ring-methylene 2.71 (dd, J=16.3, 5.9 Hz, 1H), exchangeable proton NH₂ correlated with ring-methylene 2.99-2.80 (m, 3H).

Compound 674″S: ¹H NMR (300 MHz, DMSO-d₆) δ 7.50 (br s, 2H), 7.32 (s, 1H), 3.85-3.55 (m, 1H), 3.30 (s, 3H), 3.08 (dd, J=17.8, 4.7 Hz, 1H), 2.92 (dd, J=17.7, 5.9 Hz, 1H), 2.80-2.55 (m, 2H), 1.90-1.75 (m, 2H).

NOESY: Ar—H 7.32 (s, 1H) correlated with ring-methylene 2.80-2.55 (m, 2H), exchangeable proton NH₂ correlated with ring-methylene 3.08 (dd, J=17.8, 4.7 Hz, 1H) and 2.92 (dd, J=17.7, 5.9 Hz, 1H).

Steps 5-6 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 189F from compound 674″F. MS-ESI: 361 (M+1).

TABLE 56 The Intermediates in the following table were prepared using the similar procedures for converting compound 674″F to Intermediate 189F shown in Scheme 134 starting from 674″S. Intermediate Exact Mass # Structure IUPAC Name [M − H]⁻ Intermediate 189S

N′-(tert-butyldimethylsilyl)-6-methoxy-4,5,6,7- tetrahydrobenzo[c]thiophene-1-sulfonimidamide 361

Intermediate 190

5-((S)-1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)-N′-(tert-butyldimethylsilyl)thiophene-2-sulfonimidamide

Steps 1-2 used similar procedures for converting compound 672″ to compound 674″ shown in Scheme 134 to afford compound 678″ from compound 676″. MS-ESI: 220 (M−1).

Step 3: 5-(2-Hydroxypropan-2-yl)thiophene-2-sulfonamide

To a stirred solution of methyl 5-sulfamoylthiophene-2-carboxylate (1.0 g, 4.52 mmol) in THF (40 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added CH₃MgBr in THF (3.0 M, 7.5 mL, 22.6 mmol) dropwise at 0° C. The reaction mixture was stirred overnight at RT, quenched with sat. NH₄Cl (40 mL) at 0° C., and then extracted with EtOAc (3×40 mL). The organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 500 mg (50%) of the title compound as a yellow solid. MS-ESI: 222 (M+1).

Step 4: 5-(Prop-1-en-2-yl)thiophene-2-sulfonamide

To a stirred solution of 5-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (500 mg, 2.25 mmol) in THF (20 mL) in a 100-mL round-bottom flask under nitrogen was added Burgess reagent (1.15 g, 4.5 mmol) in portions at RT. The reaction mixture was stirred overnight at RT. The reaction mixture was quenched with H₂O (10 mL) and extracted with EtOAc (3×20 mL). The organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by prep-TLC (PE/EtOAc=1:2). This resulted in 420 mg (91.5%) of the title compound as a white solid. MS-ESI: 204 (M+1).

Step 5: 5-(1,2-Dihydroxypropan-2-yl)thiophene-2-sulfonamide

To a stirred solution of 5-(prop-1-en-2-yl)thiophene-2-sulfonamide (420 mg, 2.06 mmol) in t-BuOH (4.0 mL) and acetone (4.0 mL) in a 50-mL round-bottom flask was added NMO (483 mg, 4.12 mmol) and the reaction solution was stirred for 15 min at RT. Then to this was added a solution of OsO₄ (53 mg, 0.21 mmol) in H₂O (3.0 mL) dropwise at RT. The reaction mixture was stirred overnight at RT. The reaction was quenched with sat. aq. Na₂S₂O₃ (5.0 mL). The mixture was extracted with 3×10 mL EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was eluted from silica gel with MeOH/DCM (7:100). This resulted in 245 mg (50%) of the title compound as yellow oil. MS-ESI: 238 (M+1).

Step 6: (S) and (R)-5-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide

5-(1,2-Dihydroxypropan-2-yl)thiophene-2-sulfonamide (681″, 245 mg) was resolved by Prep-Chiral HPLC using the following conditions: CHIRALPAK AD-H SFC, 5*25 cm, 5 um; Mobile Phase A: CO₂, Mobile Phase B: MeOH:ACN=1:1 (2 mM NH₃-MeOH); Flow rate: 150 mL/min; Gradient: 50% B; 220 nm; Rt₁: 4.1 min (681″F); Rt₂: 7.4 min (681″S). This resulted in 100 mg (99% ee) of 681″F and 110 mg (98% ee) of 681″S, both as yellow oil. Absolute stereochemistry of both were unconfirmed. MS-ESI: 236 (M−1).

Step 7: (S)-2-hydroxy-2-(5-sulfamoylthiophen-2-yl)propyl 4-methylbenzenesulfonate

To a stirred solution of (S)-5-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide (681″F, 100 mg, 0.42 mmol) in pyridine (8.0 mL) in a 50-mL round-bottom flask was added TsCl (239 mg, 1.26 mmol) at RT. The reaction mixture was stirred for 16 h at RT, diluted with 20 mL of H₂O, and then extracted with 3×20 mL of EtOAc. The organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:10). This resulted in 125 mg (76%) of the title compound as yellow oil. MS-ESI: 392 (M+1).

Step 8: (S)-5-(1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)thiophene-2-sulfonamide

To a stirred solution of 2-(benzyloxy)ethan-1-ol (243 mg, 1.6 mmol) in THF(10 mL) in a 50-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 128 mg, 3.2 mmol) at 0° C. The reaction mixture was stirred for 30 min at 0° C., followed by the addition of (S)-2-hydroxy-2-(5-sulfamoylthiophen-2-yl)propyl 4-methylbenzenesulfonate (125 mg, 0.32 mmol) at 0° C. The reaction mixture was stirred for 32 h at 35° C. The reaction was quenched with H₂O (10 mL) at 0° C. The mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×10 mL) and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:2). This resulted in 113 mg (95%) of the title compound as yellow oil. MS-ESI: 372 (M+1).

Steps 9-10 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 190 from compound 683″F. MS-ESI: 485 (M+1).

TABLE 57 The intermediates in the following table were prepared using the similar procedures for converting compound 681″F to Intermediate 190 shown in Scheme 135 starting from 586″B. Exact Intermediate Mass # Structure IUPAC Name [M − H]⁻ Intermediate 191

N′-(tert-butyldimethylsilyl)-2-((S)-16-hydroxy-1-phenyl- 2,5,8,11,14-pentaoxaheptadecan-16-yl)thiazole-5- sulfonimidamide 618

Intermediate 192

Tert-butyl (1-(4-(N-(tert-butyldimethylsilyl)sulfamidimidoyl)-3-fluorophenyl)ethyl)(cyclobutyl)carbamate

Steps 1-2 used similar procedures for converting compound 654″ to compound 656″ shown in Scheme 132 to afford compound 687″ from compound 685″. MS-ESI: 274 (M+1).

Step 3: N-(tert-butyl)-4-(1-(cyclobutylamino)ethyl)-2-fluorobenzenesulfonamide

To a stirred solution 4-acetyl-N-tert-butyl-2-fluorobenzenesulfonamide (3.6 g, 13 mmol) in DCM (100 mL) in a 250-mL round-bottom flask under nitrogen were added cyclobutylamine (1.87 g, 26 mmol) at RT, followed by the addition of HCOOH (1.33 g, 29 mmol) dropwise at RT. The reaction solution was stirred overnight at RT. To the above solution was added NaBH(OAc)₃ (5.86 g, 28 mmol) in portions at RT. The reaction mixture was stirred for additional 2 days at 35° C. The mixture was adjusted to pH 9 with NaOH (2 M). The mixture was extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by prep-TLC (PE/EtOAc 2:1). This resulted in 1.5 g (35%) of the title compound as a yellow solid. MS-ESI: 329 (M+1).

Step 4: 4-(1-(Cyclobutylamino)ethyl)-2-fluorobenzenesulfonamide

To a stirred solution of N-(tert-butyl)-4-(1-(cyclobutylamino)ethyl)-2-fluorobenzenesulfonamide (1.5 g, 4.57 mmol) in DCM (20 mL) in a 250-mL round-bottom flask was added BCl₃ in DCM (1 M, 20 mL, 20 mmol) dropwise at 0° C. The reaction solution was stirred for 2 h at RT. The residue was adjusted to pH 9 with NaOH (2 M). The mixture was extracted with EtOAc (3×80 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. This resulted in 1.2 g (crude) of the title compound as yellow oil. MS-ESI: 273 (M+1).

Steps 5-7 used similar procedures for converting compound 662″ to Intermediate 187 shown in Scheme 132 to afford Intermediate 192 from compound 689″. MS-ESI: 486 (M+1).

Intermediate 193

N′-(tert-butyldimethylsilyl)-4-((cyclobutyl(methyl)amino)methyl)-2-fluorobenzenesulfonimidamide Step 1: 4-(N-(tert-butyl)sulfamoyl)-3-fluorobenzoic acid

To a stirred solution of 4-bromo-N-tert-butyl-2-fluorobenzenesulfonamide (7.7 g, 25 mmol) in THF (40 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 20 mL, 50 mmol) dropwise at −78° C. The reaction solution was stirred for 30 min at −78° C. CO₂ (g) was bubbled into the above solution for 20 min at −30° C. The reaction mixture was stirred for additional 3 h at RT. The pH value of the solution was adjusted to 10 with NaOH (1 M). The mixture was extracted with 3×30 mL of DCM. The pH value of the solution was adjusted to 3 with HCl (1 M). The mixture was extracted with 3×100 mL of EtOAc. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. This resulted in 5.0 g (74%) of the title compound as a yellow solid. MS-ESI: 274 (M−1).

Step 2: 4-(N-(tert-butyl)sulfamoyl)-N-cyclobutyl-3-fluoro-N-methylbenzamide

To a stirred solution of 4-(N-(tert-butyl)sulfamoyl)-3-fluorobenzoic acid (4.9 g, 18 mmol) in DCM (50 mL) in a 250-mL round-bottom flask were added N-methylcyclobutanamine (1.83 g, 21.6 mmol), HATU (8.8 g, 23 mmol) and TEA (5.4 g, 53 mmol). The reaction mixture was stirred overnight at RT. The reaction was quenched with H₂O (50 mL). The mixture was extracted with DCM (3×80 mL). The organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (2/3). This resulted in 2.58 g (42%) of the title compound as a yellow solid. MS-ESI: 343 (M+1).

Step 3 used similar procedures for converting compound 688″ to compound 689″ shown in Scheme 136 to afford compound 694″ from compound 693″. MS-ESI: 287 (M+1).

Step 4: 4-((Cyclobutyl(methyl)amino)methyl)-2-fluorobenzenesulfonamide

To a stirred solution of N-cyclobutyl-3-fluoro-N-methyl-4-sulfamoylbenzamide (2.2 g, 7.7 mmol) in THF (30 mL) in a 100-mL round-bottom flask under nitrogen was added BH₃-THF (1 M, 15 mL, 15 mmol) at 0° C. The reaction mixture was stirred for 30 min at 0° C. The reaction mixture was stirred overnight at RT. The reaction was quenched with aq. HCl (2 M, 50 mL) at 0° C. The reaction mixture was stirred for 10 min at RT. The pH value of the solution was adjusted to 9 with NaOH (5 M). The mixture was extracted with 3×50 mL of EtOAc and the organic layers were combined. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. This resulted in 1.74 g (83%) of the title compound as a yellow solid. MS-ESI: 273 (M+1).

Steps 5-6 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 193 from compound 695″. MS-ESI: 386 (M+1).

Intermediate 194

N-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)thiophene-2-sulfonimidamide

Step 1 used similar procedures for converting compound 654″ to compound 655″ shown in Scheme 132 to afford compound 698″ from compound 697″. MS-ESI: 297/299 (M+1).

Step 2: N-(tert-butyl)-5-((dimethylamino)methyl)thiophene-2-sulfonamide

To a stirred solution of 5-bromo-N-(tert-butyl)thiophene-2-sulfonamide (1.15 g, 3.86 mmol) in dioxane (30 mL) and H₂O (3.0 mL) in a 100-mL round-bottom flask under nitrogen were added N,N-dimethyl-1-(trifluoro-λ₄-boraneyl)methanamine, potassium salt (764 mg, 4.63 mmol) and Cs₂CO₃ (3.77 g, 11.7 mmol) in portions at RT. Then Ruphos (360 mg, 0.77 mmol) and Pd(AcO)₂ (173 mg, 0.77 mmol) were added to the mixture. The reaction mixture was stirred overnight at 100° C. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (2/1). This resulted in 120 mg (11%) of the title compound as yellow oil. MS-ESI: 277 (M+1).

Step 3 used similar procedures for converting compound 688″ to compound 689″ shown in Scheme 136 to afford compound 700″ from compound 699″. MS-ESI: 221 (M+1).

Steps 4-5 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 194 from compound 700″. MS-ESI: 334 (M+1).

Intermediate 195F

Tert-butyl (2S)-2-(5-(N-(tert-butyldimethylsilyl)sulfamidimidoyl)thiophen-2-yl)pyrrolidine-1-carboxylate Step 1: Tert-butyl (4-(5-(N-(tert-butyl)sulfamoyl)thiophen-2-yl)-4-oxobutyl)carbamate

To a stirred solution of 5-bromo-N-(tert-butyl)thiophene-2-sulfonamide (5.0 g, 16.8 mmol) in THF (50 mL) in a 250-mL 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 13 mL, 32.5 mmol) dropwise at −78° C. The reaction mixture was stirred for 1 h at −78° C. Then to the mixture was added tert-butyl 2-oxopyrrolidine-1-carboxylate (6.21 g, 33.6 mmol) at −78° C. The reaction mixture was stirred for 2 h at RT and then quenched with H₂O (50 mL). The mixture was extracted with EtOAc (3×100 mL). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 1.8 g (27%) of the title compound as a yellow solid. MS-ESI: 405 (M+1).

Step 2: N-(tert-butyl)-5-(3,4-dihydro-2H-pyrrol-5-yl)thiophene-2-sulfonamide

A solution of tert-butyl (4-(5-(N-(tert-butyl)sulfamoyl)thiophen-2-yl)-4-oxobutyl)carbamate (1.8 g, 4.45 mmol) in formic acid (20 mL) in a 100-mL round-bottom flask under nitrogen was stirred for 12 h at RT. The pH value of the solution was adjusted to 9 with sat.Na₂CO₃ (aq). The mixture was extracted with EtOAc (3×100 mL) and the organic layers were combined. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 1.0 g (78%) of the title compound as a yellow solid. MS-ESI: 287 (M+1).

Step 3: 5-(3,4-Dihydro-2H-pyrrol-5-yl)thiophene-2-sulfonamide

To a stirred solution of N-(tert-butyl)-5-(3,4-dihydro-2H-pyrrol-5-yl)thiophene-2-sulfonamide (1.0 g, 3.49 mmol) in DCM (10 mL) in a 100-mL round-bottom flask was added BCl₃ in DCM (1 M, 10 mL, 10 mmol) dropwise at 0° C. The reaction mixture was stirred for 2 h at RT. The reaction was quenched with 10 mL of MeOH. The mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 600 mg (75%) of the title compound as a yellow solid. MS-ESI: 231 (M+1).

Step 4: 5-(Pyrrolidin-2-yl)thiophene-2-sulfonamide

To a stirred solution of 5-(3, 4-dihydro-2H-pyrrol-5-yl)thiophene-2-sulfonamide (600 mg, 2.6 mmol) in MeOH (10 mL) in a 50-mL round-bottom flask under nitrogen was added NaBH₄ (197 mg, 5.21 mmol) in portions at 0° C. The reaction mixture was stirred for 2 h at RT. The reaction mixture was diluted with 10 mL of water. The mixture was extracted with 3×50 mL of EtOAc and the organic layers were combined. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. This resulted in 500 mg (83%) of the title compound as yellow oil. MS-ESI: 233 (M+1).

Step 5 used similar procedures for converting compound 662″ to compound 663″ shown in Scheme 132 to afford compound 706″ from compound 705″. MS-ESI: 331 (M−1).

Step 6: Tert-butyl (S)-2-(5-sulfamoylthiophen-2-yl)pyrrolidine-1-carboxylate and tert-butyl (R)-2-(5-sulfamoylthiophen-2-yl)pyrrolidine-1-carboxylate

Tert-butyl 2-(5-sulfamoylthiophen-2-yl)pyrrolidine-1-carboxylate (706″, 600 mg) was resolved by Prep-SFC using the following conditions: Column, CHIRALPAK AD-H SFC, 5*25 cm, 5 urn; Mobile Phase A: CO₂, Mobile Phase B: MeOH (2 mM NH₃-MeOH); Flow rate: 200 mL/min; Gradient: 24% B; UV 254 nm; Rt₁: 3.5 min (706″F); Rt₂: 5.6 min (706″S). This resulted in 250 mg (98% ee) of 706″F and 240 mg (99% ee) of 706″S, both as a yellow solid. Absolute stereochemistry of both enantiomers were assigned arbitrarily. MS-ESI: 333 (M+1).

Steps 7-8 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 195F from compound 706″F. MS-ESI: 446 (M+1).

TABLE 58 The intermediates in the following table were prepared using the similar procedures for converting compound 706″F to Intermediate 195F shown in Scheme 139 starting from 706″S. Exact Intermediate Mass # Structure IUPAC Name [M − H]⁻ Intermediate 195S

Tert-butyl (2R)-2-(5-(N-(tert- butyldimethylsilyl)sulfamidimidoyl)thiophen-2-yl)pyrrolidine-1- carboxylate 446

Intermediate 196

N′-(tert-butyldimethylsilyl)-2-(2,2,3,3,6,9,9,10,10-nonamethyl-4,8-dioxa-3,9-disilaundecan-6-yl)thiazole-5-sulfonimidamide Step 1: Diethyl 2-(thiazol-2-yl)malonate

To a stirred solution of ethyl 2-(1,3-thiazol-2-yl)acetate (5.0 g, 29 mmol) in THF (20 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 2.34 g, 58 mmol) in portions at 0° C. The reaction mixture was stirred for 30 min at 0° C. Then diethyl carbonate (50 mL) was added to the above mixture. The reaction mixture was stirred for 10 h at 65° C. The reaction was quenched with 50 mL of water and extracted with 3×50 mL of EtOAc. The organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under vacuum. This resulted in 7.59 g (crude) of the title compound as a light yellow solid. MS-ESI: 244 (M+1).

Step 2: Diethyl 2-methyl-2-(thiazol-2-yl)malonate

To a stirred solution of diethyl 2-(thiazol-2-yl)malonate (2.0 g, 8.22 mmol) in THF (30 mL) in a 250-mL 3-necked round-bottom flask under nitrogen were added DBU (2.5 g, 16 mmol) at RT, followed by the addition of CH₃I (4.67 g, 33 mmol) dropwise at 0° C. The reaction mixture was stirred for 2 h at RT and then quenched with 20 mL of water/ice. The mixture was extracted with 3×50 mL of EtOAc and the organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The crude product was purified by TLC with EtOAc/PE (1/2). This resulted in 1.1 g (52%) of the title compound as light yellow oil. MS-ESI: 258 (M+1).

Step 3: 2-Methyl-2-(thiazol-2-yl)propane-1,3-diol

To a stirred solution of diethyl 2-methyl-2-(thiazol-2-yl)malonate (1.1 g, 4.23 mmol) in THF (25 mL) in a 250-mL 3-necked round-bottom flask under nitrogen was added DIBAL-H in hexane (1 M, 25 mL, 25 mmol) in portions at 0° C. in an ice/water bath over 10 min. The reaction mixture was stirred for 2 h at RT. The reaction was then quenched with 20 mL of MeOH. The mixture was concentrated under vacuum. The crude product was purified by RP-HPLC with ACN/H₂O (9/1). This resulted in 384 mg (60%) of the title compound as light yellow oil. MS-ESI: 174 (M+1).

Step 4: 2,2,2,3,3,6,9,9,10,10-Nonamethyl-4,8-dioxa-3,9-disilaundecan-6-yl)thiazole

To a stirred solution of 2-methyl-2-(thiazol-2-yl)propane-1,3-diol (384 mg, 2.22 mmol) in THF (10 mL) in a 50-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 532 mg, 13.3 mmol) in portions at 0° C. in an ice/water bath. The reaction mixture was stirred for 10 min at 0° C. To the above mixture was added TBSCl (3.34 g, 22 mmol) in portions at 0° C. The reaction mixture was stirred for 4 h at RT. The reaction was quenched with 20 mL of water/ice. The mixture was extracted with 3×50 mL of EtOAc and the organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under vacuum. This resulted in 846 mg (crude) of the title compound as light yellow oil. MS-ESI: 402 (M+1).

Steps 5-8 used similar procedures for converting compound 642″ to Intermediate 184 shown in Scheme 129 to afford Intermediate 196 from compound 712″. MS-ESI: 594 (M+1).

Intermediate 197

N′-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)thiazole-5-sulfonimidamide Step 1: Ethyl 2-methyl-2-(thiazol-2-yl)propanoate

To a stirred solution of ethyl 2-(thiazol-2-yl)acetate (2.5 g, 14.6 mmol) in THF (30 mL) in a 100-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral, 3.5 g, 87.6 mmol) in portions at 0° C. The reaction mixture was stirred for 10 min at RT. Then to the above was added CH₃I (21 g, 146 mmol) dropwise at 0° C. The reaction mixture was stirred overnight at RT. The reaction was quenched with ice/water at 0° C. The mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×30 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:10). This resulted in 1.1 g (38%) of the title compound as a yellow solid. MS-ESI: 200 (M+1).

Step 2: 2-Methyl-2-(thiazol-2-yl)propan-1-ol

To a stirred solution of ethyl 2-methyl-2-(thiazol-2-yl)propanoate (1.3 g, 6.5 mmol) in THF (15 mL) in a 50-mL round-bottom flask was added NaBH₄ (1.48 g, 39 mmol) in portions at 0° C. The reaction mixture was stirred for 2 h at 0° C. The reaction was quenched with ice/water at 0° C. The mixture was extracted with 3×50 mL of EtOAc. The organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 600 mg (58%) of the title compound as a yellow solid. MS-ESI: 158 (M+1).

Steps 3-7 used similar procedures for converting compound 711″ to Intermediate 196 shown in Scheme 140 to afford Intermediate 197 from compound 718″. MS-ESI: 464 (M+1).

Intermediate 198

N′-(tert-butyldimethylsilyl)-5-phenylthiophene-2-sulfonimidamide Step 1: 5-Phenylthiophene-2-sulfonamide

To a stirred solution of 5-bromothiophene-2-sulfonamide (500 mg, 2.07 mmol) in dioxane (20 mL) and H₂O (2.0 mL) in a 50 mL 3-necked round-bottom flask under nitrogen were added phenylboronic acid (504 mg, 4.13 mmol), Pd(dppf)Cl₂ (151 mg, 0.21 mmol) and Cs₂CO₃ (1.35 g, 4.13 mmol) at RT. The reaction mixture was stirred overnight at 100° C. The reaction was diluted with H₂O (20 mL) and the mixture was extracted with 3×20 mL of EtOAc. The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (5:1). This resulted in 450 mg (91%) as a white solid. MS-ESI: 238 (M−1).

Steps 2-3 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 198 from compound 724. MS-ESI: 353 (M+1).

Intermediate 199

N-(tert-butyldimethylsilyl)-5-(2-hydroxyphenyl)thiophene-2-sulfonimidamide

Steps 1-2 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford compound 727″ from compound 723″. MS-ESI: 355/357 (M+1).

Step 3 used similar procedures for converting compound 723″ to compound 724″ shown in Scheme 142 to afford Intermediate 199 from compound 727″. MS-ESI: 369 (M+1).

TABLE 59 The intermediates in the following table were prepared using the similar procedures for converting compound 723″ to Intermediate 199 shown in Scheme 143. Exact Intermediate Mass # Structure IUPAC Name [M − H]⁻ Intermediate 200

N-(tert-butyldimethylsilyl)-5-(2- (hydroxymethyl)phenyl)thiophene-2-sulfonimidamide 383

Intermediate 201

N′-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide Step 1: Ethyl 2-mercaptothiazole-4-carboxylate

To a stirred solution of ethyl 2-bromothiazole-4-carboxylate (100 g, 424 mmol) in EtOH (1.0 L) in a 2000-mL round-bottom flask was added NaSH (119 g, 2.12 mol) in portions at RT. The reaction mixture was stirred for 3 h at 85° C. and then concentrated under vacuum. The residue was dissolved in 500 mL of H₂O. The pH value of the solution was adjusted to 3 with HCl (1 M). The solids were collected by filtration. This resulted in 80 g (99.8%) of the title compound as a yellow solid. MS-ESI: 190 (M+1).

Step 2: Ethyl 2-(chlorosulfonyl)thiazole-4-carboxylate

To a stirred solution of ethyl 2-mercaptothiazole-4-carboxylate (80 g, 421 mmol) in HCl (12 M, 800 mL) and AcOH (800 mL) in a 5000-mL round-bottom flask was added NaClO in H₂O (13% wt., 1.2 L, 1.78 mol) dropwise at 0° C. The reaction mixture was stirred for 2 h at 0° C. The residue was dissolved in 1.6 L of H₂O. The mixture was extracted with 2×2.0 L of DCM. The organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. This resulted in 36 g (crude) of the title compound as yellow oil.

Step 3: Ethyl 2-sulfamoylthiazole-4-carboxylate

To a stirred solution of ethyl 2-(chlorosulfonyl)thiazole-4-carboxylate (36 g, crude) in DCM (500 mL) in a 1.0-L round-bottom flask was introduced NH₃(g) bubbled for 20 min at 0° C. The reaction mixture was stirred for 1 h at 0° C. The mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 18 g (18%, over two steps) of the title compound as a white solid. MS-ESI: 235 (M−1).

Step 4: 4-(Hydroxymethyl)thiazole-2-sulfonamide

To a stirred solution of ethyl 2-sulfamoylthiazole-4-carboxylate (12 g, 51 mmol) in EtOH (500 mL) in a 1-L round-bottom flask under nitrogen was added NaBH₄ (15.5 g, 408 mmol) in portions at 0° C. The reaction mixture was stirred for 4 h at 0° C. The reaction was quenched with 100 mL of water/ice. The reaction mixture was concentrated under vacuum. The pH value of the mixture was adjusted to 5 with HCl (6 M). The mixture was concentrated under vacuum. The solids were dissolved with MeOH (200 mL). The residue was eluted from silica gel with EtOAc (100%). This resulted in 8.0 g (81%) of the title compound as a white solid. MS-ESI: 193 (M−1).

Step 5: N-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole-2-sulfonamide

To a stirred solution of 4-(hydroxymethyl)thiazole-2-sulfonamide (4.6 g, 24 mmol) in THF (100 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 7.68 g, 192 mmol) in several batches at 0° C. The mixture was stirred for 10 min at RT, followed by the addition of TBSCl (10.8 g, 72 mmol) in portions at 0° C. The reaction mixture was stirred for 1 h at RT. The reaction was quenched with ice/water (100 mL). The mixture was extracted with EtOAc (3×100 mL). The organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 4.5 g (45%) of the title compound as yellow oil. MS-ESI: 421 (M−1).

Step 6: N-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(2-hydroxypropan-2-yl) thiazole-2-sulfonamide

To a stirred solution of N-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole-2-sulfonamide (3.0 g, 7.1 mmol) in THF (20 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 5.7 mL, 14.2 mmol) dropwise at −78° C. The reaction solution was stirred for 1 h at −78° C. Then to this solution was added acetone (4.2 g, 71 mmol) at −78° C. The reaction mixture was stirred for 1 h at −78° C. The reaction was quenched with 20 mL of water/ice. The mixture was extracted with 3×100 mL of EtOAc. The organic layers was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (10:1). This resulted in 1.48 g (43%) of the title compound as yellow oil. MS-ESI: 481 (M+1).

Step 7 used similar procedures for converting compound 640″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 201 from compound 734″. MS-ESI: 480 (M+1).

Intermediate 202

N′-(tert-butyldimethylsilyl)-1-ethyl-1H-pyrazole-3-sulfonimidamide Step 1: 1-Ethyl-3-nitro-1H-pyrazole

To a stirred solution of 3-nitro-1H-pyrazole (20 g, 177 mmol) in DMF (100 mL) in a 250-mL round-bottom flask were added K₂CO₃ (49 g, 354 mmol) in portions at RT, followed by the addition of iodoethane (55 g, 354 mmol) dropwise at RT. The reaction mixture was stirred for 16 h at 80° C. in an oil bath. The reaction mixture was diluted with 200 mL of H₂O. The mixture was extracted with 3×200 mL of EtOAc and the organic layers were combined and dried over anhydrous Na₂SO₄. The mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:4). This resulted in 22.6 g (91%) of the title compound as yellow oil. MS-ESI: 142 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.06 (d, J=2.5 Hz, 1H), 7.04 (d, J=2.5 Hz, 1H), 4.27 (q, J=7.3 Hz, 2H), 1.42 (t, J=7.3 Hz, 3H).

Step 2: 1-Ethyl-1H-pyrazol-3-amine

To a stirred solution of 1-ethyl-3-nitro-1H-pyrazole (22 g, 156 mmol) in MeOH (100 mL) in a 250-mL round-bottom flask under nitrogen was added Pd/C (10% wt., 2.2 g) in portions at 0° C. The flask was evacuated and refilled three times with hydrogen. The reaction mixture was stirred overnight at RT under atmosphere of hydrogen with a balloon. The solids were filtered out. The filtrate was concentrated under vacuum. This resulted in 13.8 g (80%) of the title compound as yellow oil. MS-ESI: 112 (M+1).

Step 3: 1-Ethyl-1H-pyrazole-3-sulfonamide

To a stirred solution of 1-ethyl-1H-pyrazol-3-amine (3.4 g, 31 mmol,) in HCl (6 M, 20 mL) in a 100-mL round-bottom flask was added NaNO₂ (2.53 g, 37 mmol) in H₂O (5.0 mL) dropwise slowly at 0° C. over 25 min. The reaction solution was stirred for 40 min at 0° C., this solution was assigned as solution A. Then CuCl₂ (8.23 g, 61 mmol) was added to a 250-mL single necked round-bottom flask with AcOH (100 mL) as the solvent, SO₂ (g) was bubbled to the mixture with stirring at 0° C. for 20 min, this mixture was assigned as solution B. To the mixture B was added solution A dropwise with stirring at 0° C. The reaction mixture was stirred for additional 2 h at 0° C. The reaction mixture was diluted with 100 mL of H₂O. The mixture was extracted with 3×150 mL of DCM. The organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was dissolved in 30 mL of DCM and NH₃ (g) was bubbled for 15 min at 0° C. The reaction was stirred for 2 h at RT. The reaction mixture was concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (3:1). This resulted in 1.75 g (33%) of the title compound as a yellow solid. MS-ESI: 174 (M−1).

Steps 4-5 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 202 from compound 738″. MS-ESI: 289 (M+1).

Intermediate 203

N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

Steps 1-2 used similar procedures for converting compound 735″ to compound 737″ shown in Scheme 145 to afford compound 742″ from compound 740″. Compound 742″ (5 g) and Compound 742″BP (0.5 g) were separated from silica gel eluted with PE/EtOAc (5:1). MS-ESI: 184 (M+1). The regiochemistry of 742″ and 742″BP were assigned based on NMR including NOESY.

Compound 742″: ¹H NMR (300 MHz, DMSO-d₆) δ 5.93 (s, 1H), 5.33-5.10 (m, 1H), 4.83 (s, 2H), 3.77 (s, 3H), 1.31 (d, J=6.3 Hz, 6H).

NOESY: exchangeable protons NH₂ 4.83 (s, 2H) has no correlation with i-Pr's CH at 5.33-5.10 (m, 1H) and O—CH₃ 3.77 (s, 3H) has correlation with i-Pr's CH₃ at 1.31 (d, J=6.3 Hz, 6H).

Compound 742″BP: ¹H NMR (300 MHz, DMSO-d₆) δ 5.72 (s, 1H), 5.35 (s, 2H), 4.59-4.32 (m, 1H), 3.71 (s, 3H), 1.30 (d, J=6.6 Hz, 6H).

NOESY: exchangeable protons NH₂ 5.35 (s, 2H) has correlation with i-Pr's CH at 4.59-4.32 (m, 1H) and O—CH₃ 3.71 (s, 3H) has no correlation with i-Pr's CH₃ at 1.30 (d, J=6.6 Hz, 6H).

Steps 3-4 used similar procedures for converting compound 737″ to compound 738″ shown in Scheme 145 to afford compound 744″ from compound 742″. MS-ESI: 246 (M−1).

Step 5: 5-(2-Hydroxypropan-2-yl)-1-isopropyl-1H-pyrazole-3-sulfonamide

To a stirred solution of methyl 1-isopropyl-3-sulfamoyl-1H-pyrazole-5-carboxylate (430 mg, 1.74 mmol) in THF (50 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added MeMgBr in THF (3.0 M, 3.5 mL, 10 mmol) at 0° C. The reaction mixture was stirred for 16 h at RT. The reaction mixture was quenched with water/ice at 0° C. The pH value of the solution was adjusted to 6 with HCl (6 M). The reaction mixture was extracted with 3×50 mL of EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (3:1). This resulted in 400 mg (93%) of the title compound as a yellow solid. MS-ESI: 246 (M−1).

Steps 6-7 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 203 from compound 745″. MS-ESI: 361 (M+1).

Intermediate 204

N′-(tert-butyldimethylsilyl)-6-(2-hydroxypropan-2-yl)pyridine-2-sulfonimidamide Step 1: Methyl 6-sulfamoylpicolinate

To a stirred solution of 6-bromopyridine-2-sulfonamide (5.0 g, 21 mmol) in MeOH (200 mL) in 500 mL-sealed tube under nitrogen were added Pd(dppf)Cl₂ (1.54 g, 2.1 mmol), Pd(PPh₃)₄ (2.44 g, 2.1 mmol) and TEA (11 g, 105 mmol) at RT. Then the sealed tube was evacuated and refilled three times with CO. The reaction mixture was stirred overnight at 80° C. under CO atmosphere (10 atm). The reaction mixture was concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:2). This resulted in 1.8 g (39%) of the title compound as a light yellow solid. MS-ESI: 215 (M−1).

Steps 2-4 used similar procedures for converting compound 744 to Intermediate 203 shown in Scheme 146 to afford Intermediate 204 from compound 748″. MS-ESI: 330 (M+1).

Intermediate 205

2-Fluoro-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)benzenesulfonimidamide

Steps 1-3 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford compound 753″ from compound 483″. MS-ESI: 367/369 (M+1).

Step 4: 4-Bromo-N-((tert-butyldimethylsilyl)-2-fluoro-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)benzenesulfonimidamide

To a stirred solution of 4-bromo-N′-(tert-butyldimethylsilyl)-2-fluorobenzenesulfonimidamide (3.0 g, 8.2 mmol) in THF (50 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 1.0 g, 25 mmol) in portions at 0° C. The reaction mixture was stirred for 10 min at RT. Then to the mixture was added 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (1.95 g, 9.8 mmol) in portions at 0° C. The reaction mixture was stirred for 1 h at RT. The reaction mixture was quenched with H₂O (50 mL) and then extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel column with EtOAc/PE (1:5). This resulted in 2.8 g (61%) of the title compound as a white solid. MS-ESI: 566/568 (M+1).

Step 5: 4-Bromo-2-fluoro-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) benzenesulfonimidamide

To a stirred solution of 4-bromo-N-(tert-butyldimethylsilyl)-2-fluoro-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide (2.8 g, 4.94 mmol) in DCM (100 mL) in a 250-mL round-bottom flask was added TFA (56 mg, 0.49 mmol) at RT. The reaction mixture was stirred for 1 h at RT and then concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:8). This resulted in 1.9 g (85%) of the title compound as a yellow solid. MS-ESI: 452/454 (M+1).

Step 6: 2-Fluoro-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4)carbamoyl)-4-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)benzenesulfonimidamide

To a stirred solution of 4-bromo-2-fluoro-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) benzenesulfonimidamide (1.9 g, 4.2 mmol) in dioxane (90 mL) and H₂O (10 mL) in a 250-mL round-bottom flask under nitrogen were added K₃PO₄ (1.78 g, 8.4 mmol), Pd(dtbpf)Cl₂ (274 mg, 0.42 mmol) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole (966 mg, 4.62 mmol) at RT. The reaction mixture was stirred for 5 h at 60° C. and then concentrated under vacuum. The resulted was dissolved in 100 mL H₂O and extracted with EtOAc (3×100 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 100 mg (5.3%) of the title compound as a yellow solid. MS-ESI: 455 (M+1).

Intermediate 206

N′-(tert-butyldimethylsilyl)-4-(1-(dimethylamino)-2-methylpropan-2-yl)benzenesulfonimidamide

Step 1: 2-Methyl-2-(4-sulfamoylphenyl)propanoic acid

To a stirred solution of ethyl 2-methyl-2-(4-sulfamoylphenyl)propanoate (7.0 g, 26 mmol) in MeOH (140 mL) and H₂O (93 mL) in a 500-mL round-bottom flask was added NaOH (10 g, 258 mmol) at 0° C. The reaction mixture was stirred for 90 min at 55° C. in an oil bath. The pH value of the mixture was adjusted to 2-3 with HCl (2 M). To the mixture was added additional 200 mL of MeOH. The solids were filtered out. The filtrate was concentrated under vacuum. This resulted in 5.0 g (80%) of the title compound as a white crude solid. MS-ESI: 242 (M−1).

Step 2: N,N,2-trimethyl-2-(4-sulfamoylphenyl)propanamide

To a stirred solution of 2-methyl-2-(4-sulfamoylphenyl)propanoic acid (3.0 g, 12 mmol) in THF (150 mL) in a 250-mL round-bottom flask were added HATU (6.8 g, 18 mmol), DIEA (3.19 g, 25 mmol) and dimethylamine (4.44 g, 99 mmol) at RT. The reaction solution was stirred for 12 h at RT. The resulting solution was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (30:1). This resulted in 2.5 g (75%) of the title compound as a white solid. MS-ESI: 269 (M−1).

Step 3: 4-(1-(Dimethylamino)-2-methylpropan-2-yl)benzenesulfonamide

To a stirred solution of N,N,2-trimethyl-2-(4-sulfamoylphenyl)propanamide (2.5 g, 9.25 mmol) in THF (30 mL) in a 250-mL 3-necked round-bottom flask under nitrogen was added DIBAL-H in hexane (1 M, 46 mL, 46.2 mmol) at −10° C. The reaction mixture was stirred for 12 h at RT. The reaction was quenched with 15 mL of MeOH. The reaction mixture was concentrated under vacuum. The residue was diluted with 200 mL of HCl (2 M). The mixture was extracted with 3×200 mL of EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 1.50 g (63%) of the title compound as a yellow solid. MS-ESI: 255 (M−1).

Steps 4-5 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 206 from compound 759″. MS-ESI: 370 (M+1).

Intermediate 207

N′-(tert-butyldimethylsilyl)-3-fluoro-5-isopropylpyridine-2-sulfonimidamide Step 1: 2-(Benzylthio)-5-bromo-3-fluoropyridine

To a stirred solution of 5-bromo-2,3-difluoropyridine (20 g, 103 mmol) in dioxane (80 mL) in a 500-mL round-bottom flask under nitrogen were added t-BuOK (11.6 g, 103 mmol) in portions at 0° C., followed by phenylmethanethiol (12.8 g, 103 mmol) in portions at RT. The reaction mixture was stirred overnight at 75° C. and then quenched with H₂O (200 mL). The mixture was extracted with EtOAc (3×200 mL). The organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 18 g (59%) of the title compound as colorless oil. MS-ESI: 298/300 (M+1).

Step 2: 2-(Benzylthio)-3-fluoro-5-(prop-1-en-2-yl)pyridine

To a stirred solution of 2-(benzylthio)-5-bromo-3-fluoropyridine (18 g, 48 mmol) in dioxane (300 mL) and H₂O (60 mL) in a 1-L round-bottom flask under nitrogen were added Cs₂CO₃ (47 g, 145 mmol) and Pd(dppf)Cl₂ (5.3 g, 7.2 mmol). Then to the above mixture was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl) -1,3,2-dioxaborolane (24 g, 145 mmol) at RT. The reaction mixture was stirred overnight at 90° C. The reaction mixture was extracted with 4×300 mL of EtOAc and the organic layers combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 10 g (80%) of the title compound as brown oil. MS-ESI: 260 (M+1).

Step 3: 2-(Benzylthio)-3-fluoro-5-isopropylpyridine

To a stirred solution of 2-(benzylthio)-3-fluoro-5-(prop-1-en-2-yl)pyridine (10 g, 39 mmol) in MeOH (20 mL) in a 300-mL sealed tube under nitrogen were added AcOH (1.0 mL) and Pd/C (10% wt., 2.1 g) at RT. The sealed tube was evacuated and refilled three times with hydrogen. The resulting mixture was stirred for 24 h at 40° C. under atmosphere of hydrogen with a balloon. The solids were filtered out. The filtrate was concentrated under vacuum. This resulted in 5.0 g (49%) of the title compound as brown oil. MS-ESI: 262 (M+1).

Step 4: 3-Fluoro-5-isopropylpyridine-2-sulfonamide

To a stirred solution of 2-(benzylthio)-3-fluoro-5-isopropylpyridine (500 mg, 1.9 mmol) in DCM (20 mL) and AcOH (20.00 mL) and H₂O (20 mL) in a 250-mL 3-necked round-bottom flask was introduced Cl₂ bubbled for 30 min at 0° C. The mixture was extracted with DCM (3×40 mL). The combined organic layers were washed with brine (3×100 mL). The organic layer was dried over anhydrous Na₂SO₄. Then the solids were filtered out, NH₃ (g) was bubbled into the filtrate for 20 min at 0° C. The reaction mixture was stirred overnight at RT. The mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc (100%). This resulted in 50 mg (12%) of the title compound as yellow oil. MS-ESI: 217 (M−1).

Steps 5-6 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 207 from compound 765″. MS-ESI: 332 (M+1).

Intermediate 208

N′-(tert-butyldimethylsilyl)-2-fluoro-4-(1-methylpiperidin-3-yl)benzenesulfonimidamide

Steps 1-2 used similar procedures for converting compound 762″ to compound 764″ shown in Scheme 150 to afford compound 769″ from compound 767″. MS-ESI: 357 (M−1).

Step 3: 2-Fluoro-4-(piperidin-3-yl)benzenesulfonamide

To a stirred solution of tert-butyl 3-(3-fluoro-4-sulfamoylphenyl)piperidine-1-carboxylate (500 mg, 1.4 mmol) in DCM (5.0 mL) in a 25-mL round-bottom flask was added HCl in dioxane (4 M, 3.5 mL, 14 mmol) dropwise at RT. The reaction mixture was stirred for 2 h at RT and then diluted with 5.0 mL of water. The mixture was extracted with 3×10 mL of DCM. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. This resulted in 400 mg (crude) of the title compound as a yellow solid. MS-ESI: 257 (M−1).

Step 4: 2-Fluoro-4-(1-methylpiperidin-3-yl)benzenesulfonamide

To a stirred solution of 2-fluoro-4-(piperidin-3-yl)benzenesulfonamide (400 mg, crude) in MeOH (5.0 mL) in a 25-mL round-bottom flask under nitrogen was added HCHO (269 mg, 8.4 mmol) in portions at RT. The resulting solution was stirred overnight at RT. Then to the solution was added NaBH₃CN (173 mg, 2.8 mmol) at RT. The reaction mixture was stirred for 2 h at RT. The mixture was concentrated under vacuum. The reaction was quenched with H₂O (10 mL). The mixture was extracted with EtOAc (3×20 mL). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 300 mg (79%) of the title compound as a yellow solid. MS-ESI: 271 (M−1).

Steps 5-6 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 208 from compound 771″. MS-ESI: 386 (M+1).

Intermediate 209

N′-(tert-butyldimethylsilyl)-3-fluoro-5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-sulfonimidamide

Steps 1-2 used similar procedures for converting compound 642″ to compound 644″ shown in Scheme 129 to afford compound 775″ from compound 773″. MS-ESI: 375 (M+1).

Step 3: Tert-butyl 2-(N-(tert-butyl)sulfamoyl)-3-fluoro-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate

To a stirred solution of tert-butyl 2-(N-(tert-butyl)sulfamoyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (4.0 g, 10.7 mmol) in THF (40 mL) in a 250-mL 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 13 mL, 32 mmol) dropwise at −78° C. The reaction mixture was stirred for 30 min at −78° C. Then to the reaction solution was added NFSI (6.74 g, 21.4 mmol) in THF (10 mL) dropwise at −78° C. The reaction mixture was stirred for 2 h at RT and then quenched with H₂O (40 mL). The mixture was extracted with EtOAc (3×100 mL) and the organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 1.7 g (41%) of the title compound as yellow oil. MS-ESI: 392 (M+1).

Step 4: N-(tert-butyl)-3-fluoro-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-sulfonamide

To a stirred solution of tert-butyl 2-(N-(tert-butyl)sulfamoyl)-3-fluoro-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (300 mg, 0.76 mmol) in DCM (5.0 mL) in a 25-mL round-bottom flask was added HCl in dioxane (4 M, 0.75 mL) dropwise at RT. The reaction mixture was stirred for 1 h at RT. The reaction mixture was concentrated under vacuum. This resulted in 200 mg (89%) of the title compound as yellow oil. MS-ESI: 293 (M+1).

Step 5: N-(tert-butyl)-3-fluoro-5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-sulfonamide

To a stirred solution of N-(tert-butyl)-3-fluoro-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-sulfonamide (200 mg, 0.68 mmol) in MeOH (2.0 mL) in a 25-mL round-bottom flask under nitrogen was added HCHO (31 mg, 1.03 mmol) in portions. The reaction mixture was stirred for 1 h at RT. To above mixture was added NaBH₃CN (64 mg, 1.03 mmol) in portions at RT. The reaction mixture was stirred for 2 h at RT. The reaction mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 200 mg (95%) of the title compound as yellow oil. MS-ESI: 307 (M+1).

Step 6 used similar procedures for converting compound 703″ to compound 704″ shown in Scheme 139 to afford compound 779″ from compound 778″. MS-ESI: 249 (M−1).

Steps 7-8 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 209 from compound 779″. MS-ESI: 364 (M+1).

Intermediate 210

Tert-butyl 2-(N-(tert-butyldimethylsilyl)sulfamidimidoyl)-3-fluoro-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate

Steps 1-4 used similar procedures for converting compound 688″ to Intermediate 192 shown in Scheme 136 to afford Intermediate 210 from compound 776″. MS-ESI: 450 (M+1).

Intermediate 211

N-(tert-butyldimethylsilyl)-5,6-dimethyl-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-sulfonimidamide Step 1: Methyl 4-(1-acetamidovinyl)thiophene-3-carboxylate

To a stirred solution of methyl 4-bromothiophene-3-carboxylate (10 g, 45 mmol) in DMF (100 mL) in a 250-mL round-bottom flask under nitrogen were added tris(2-methoxyphenyl)phosphine (3.19 g, 9.05 mmol) and N-vinylacetamide (2.24 g, 226 mmol) at RT. To the above mixture were added Pd(AcO)₂ (1.02 g, 4.5 mmol) and TEA (6.0 mL, 43 mmol) at RT. Then the reaction mixture was stirred overnight at 80° C. The reaction mixture was quenched with H₂O (100 mL). The mixture was extracted with EtOAc (3×200 mL) and the organic layers were combined. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in 6.0 g (60%) of the title compound as yellow liquid. MS-ESI: 226 (M+1).

Step 2: Methyl 4-(1-acetamidoethyl)thiophene-3-carboxylate

To a stirred solution of methyl 4-(1-acetamidovinyl)thiophene-3-carboxylate (5.0 g, 22 mmol) in MeOH (100 mL) in a 250-mL round-bottom flask under nitrogen was added Pd/C (10% wt., 500 mg) in portions at 0° C. The flask was evacuated and refilled three times with hydrogen. The reaction mixture was stirred for 2 days at RT under atmosphere of hydrogen with a balloon. The reaction mixture was filtered and the filter cake was washed with MeOH (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in 3.3 g (66%) of the title compound as a yellow solid. MS-ESI: 228 (M+1).

Step 3: 4-(1-Acetamidoethyl)thiophene-3-carboxylic acid

A solution of methyl 4-(1-acetamidoethyl)thiophene-3-carboxylate (3.2 g, 14 mmol) in HCl (2 M, 30 mL) in a 100-mL round-bottom flask under nitrogen was stirred overnight at 100° C. The resulting mixture was concentrated under vacuum. This resulted in 3.0 g (crude) of the title compound as a brown solid. MS-ESI: 212 (M−1).

Step 4: 6-Methyl-5,6-dihydro-4H-thieno[3,4-c]pyrrol-4-one

To a stirred solution of 4-(1-acetamidoethyl)thiophene-3-carboxylic acid (3.0 g, crude) in DCM (200 mL) were added HATU (8.02 g, 21 mmol) and TEA (4.27 g, 42 mmol) in portions at RT. The reaction mixture was stirred overnight at RT. The reaction mixture was concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in 1.9 g (88%, over two steps) of the title compound as a light yellow solid. MS-ESI: 154 (M+1).

Step 5 used similar procedures for converting compound 770″ to compound 771″ shown in Scheme 151 to afford compound 789″ from compound 788″. MS-ESI: 168 (M+1).

Steps 6-7 used similar procedures for converting compound 672″ to compound 674″ shown in Scheme 134 to afford compound 791″ from compound 789″. MS-ESI: 245 (M−1).

Step 8: 5,6-Dimethyl-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-sulfonamide

To a stirred solution of 5,6-dimethyl-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-sulfonamide (486 mg, 1.97 mmol) in THF (5.0 mL) under nitrogen was added LiAlH₄ (225 mg, 5.91 mmol) in portions at 0° C. The reaction mixture was stirred overnight at 70° C. The reaction mixture was quenched with H₂O (0.3 mL) and aq. NaOH (25% wt., 0.3 mL) at 0° C. The mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (12:1). This resulted in 300 mg (65%) of the title compound as yellow oil. MS-ESI: 231 (M−1).

Steps 9-10 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 211 from compound 792″. MS-ESI: 346 (M+1).

Intermediate 212

N′-(tert-butyldimethylsilyl)-3-fluoro-6,7-dihydro-4H-thieno[3,2-c]pyran-2-sulfonimidamide Step 1: 4-Fluorothiophene-2-carbaldehyde

To a stirred solution of (4-fluorothiophen-2-yl)methanol (7.5 g, 56.8 mmol) in DCM (300 mL) in a 1 L round-bottom flask under nitrogen was added Dess-Martin reagent (48 g, 113 mmol) in portions at 0° C. The reaction mixture was stirred for 1 h at RT and then quenched with sat. aq. Na₂S₂O₃ (200 mL). The mixture was extracted with DCM (3×200 mL) and the organic layer combined. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in 6.75 g (91%) of the title compound as yellow oil. MS-ESI: 131 (M+1).

Step 2: (E)-4-fluoro-2-(2-methoxyvinyl)thiophene

To a stirred solution of 4-fluorothiophene-2-carbaldehyde (5.0 g, 38.4 mmol) in THF (300 mL) in a 1 L round-bottom flask under nitrogen were added (methoxymethyl)triphenylphosphanium chloride (20 g, 58 mmol) in portions at 0° C., followed by the addition of t-BuOK (6.47 g, 58 mmol) in portions at 0° C. The reaction mixture was stirred for 4 h at 15° C., quenched with H₂O (200 mL), and extracted with EtOAc (3×200 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:9). This resulted in 5.0 g (82%) of the title compound as brown oil. MS-ESI: 159 (M+1).

Step 3: 2-(4-Fluorothiophen-2-yl)acetaldehyde

To a stirred solution of (E)-4-fluoro-2-(2-methoxyvinyl)thiophene (5.0 g, 32 mmol) in dioxane (36 mL) in a 250 mL round-bottom flask was added aq. HCl (4 M, 36 mL) at 0° C. The reaction mixture was stirred for 4 h at 15° C. The mixture was extracted with EtOAc (3×100 mL) and the organic layers were combined and concentrated under vacuum. This resulted in 1.5 g (33%) of the title compound as brown oil. MS-ESI: 145 (M+1).

Step 4 used similar procedures for converting compound 731″ to compound 732″ shown in Scheme 144 to afford compound 797″ from compound 796″. MS-ESI: 147 (M+1).

Step 5: 3-Fluoro-6,7-dihydro-4H-thieno[3,2-c]pyran

To a stirred solution of 2-(4-fluorothiophen-2-yl)ethan-1-ol (300 mg, 2.05 mmol) in ACN (30 mL) in a 100-mL round-bottom flask were added InCl₃ (902 mg, 4.1 mmol) at RT, followed by the addition of paraformaldehyde (131 mg, 4.1 mmol) in portions at RT. The reaction mixture was stirred overnight at 70° C. The reaction mixture was quenched with H₂O (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (8:92). This resulted in 240 mg (74%) of the title compound as colorless oil. MS-ESI: 159 (M+1).

Step 6: 3-Fluoro-6,7-dihydro-4H-thieno[3,2-c]pyran-2-sulfonyl chloride

To a stirred solution of 3-fluoro-6,7-dihydro-4H-thieno[3,2-c]pyran (300 mg, 1.9 mmol) in 1,2-dichloroethane (50 mL) in a 100-mL round-bottom flask was added sulfur trioxide DMF complex (349 mg, 2.28 mmol) in portions at RT. The reaction mixture was stirred for 30 min at RT. To above mixture was added SOCl₂ (271 mg, 2.3 mmol) dropwise at 0° C. The reaction mixture was stirred overnight at 50° C. and then concentrated under vacuum. This resulted in 260 mg (crude) of the title compound as a yellow solid.

Step 7: 3-Fluoro-6,7-dihydro-4H-thieno[3,2-c]pyran-2-sulfonamide

To a stirred solution of 3-fluoro-6,7-dihydro-4H-thieno[3,2-c]pyran-2-sulfonyl chloride (260 mg, crude) in DCM (10 mL) in a 50-mL round-bottom flask was introduced NH₃ (g) bubbled for 10 min at 0° C. The reaction mixture was stirred for 2 h at 15° C. The reaction mixture was quenched with H₂O (10 mL). The mixture was extracted with DCM (3×10 mL) and the organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 200 mg (44%, over two steps) of the title compound as a yellow solid. MS-ESI: 236 (M−1).

Steps 8-9 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 212 from compound 800″. MS-ESI: 351 (M+1).

Intermediate 213

N′-(tert-butyldimethylsilyl)-1-(difluoromethyl)-4-fluoro-1H-pyrazole-3-sulfonimidamide Step 1: 4-Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

To a stirred solution of 4-fluoro-1H-pyrazole (10 g, 116 mmol) in DMF (100 mL) under nitrogen was added NaH (60% wt., dispersion in mineral oil, 10.7 g, 267 mmol) at 0° C. over 10 min. The reaction mixture was stirred for 30 min at 10° C. To this mixture was added SEM-Cl (45 g, 267 mmol) dropwise at 0° C. over 10 min. The reaction mixture was stirred overnight at 7° C. The reaction was quenched with 100 mL of water, extracted with 3×100 mL of EtOAc. The organic layers were combined, washed with 5×100 mL of brine, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:100). This resulted in 27.4 g (crude) of the title compound as a light yellow liquid. MS-ESI: 217 (M+1).

Steps 2-3 used similar procedures for converting compound 719″ to compound 720″ shown in Scheme 141 to afford compound 805″ from compound 803″.

Step 4: N,N-dibenzyl-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-sulfonamide

To a stirred solution of 4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-sulfonyl chloride (20.4 g, 65 mmol) in DCM (200 mL) was added Et₃N (8.85 g, 87 mmol) dropwise with stirring at 0° C. over 5 min. To this mixture was added dibenzylamine (17 g, 84 mmol) dropwise with stirring at 0° C. over 5 min. The reaction mixture was stirred for 1 h at 8° C. The reaction was quenched with 300 mL of water. The mixture was extracted with 3×300 mL of DCM and the organic layers were combined. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:19). This resulted in 22.5 g (73%) of the title compound as light yellow oil. MS-ESI: 346 (M+1).

Step 5: N,N-dibenzyl-4-fluoro-1-(hydroxymethyl)-1H-pyrazole-5-sulfonamide

To a stirred solution of N,N-dibenzyl-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-sulfonamide (22.5 g, 47.3 mmol) in DCM (25 mL) was added TFA (25 mL) dropwise at RT. The reaction mixture was stirred overnight at RT and then concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:4). This resulted in 15 g (84%) of the title compound as yellow oil. MS-ESI: 376 (M+1).

Step 6: N,N-dibenzyl-4-fluoro-1H-pyrazole-5-sulfonamide

To a stirred solution of N,N-dibenzyl-4-fluoro-1-(hydroxymethyl)-1H-pyrazole-5-sulfonamide (15 g, 40 mmol) in dioxane (50 mL) was added NH₃.H₂O (30% wt., 50 mL) dropwise at RT. The reaction mixture was stirred for 3 h at RT and then concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 12 g (87%) of the title compound as a white solid. MS-ESI: 346 (M+1).

Step 7: N,N-dibenzyl-1-(difluoromethyl)-4-fluoro-1H-pyrazole-3-sulfonamide

To a stirred solution of N,N-dibenzyl-4-fluoro-1H-pyrazole-5-sulfonamide (6.6 g, 19 mmol) in DMF (100 mL) were added Cs₂CO₃ (18.7 g, 57 mmol) in portions at RT, followed by the addition of sodium 2-chloro-2,2-difluoroacetate (4.38 g, 29 mmol) in portions at RT. The reaction mixture was stirred for 3 h at 110° C. The reaction mixture was quenched with 100 mL of water/ice at 0° C. The mixture was extracted with 3×100 mL of EtOAc and the organic layers were combined. The organic layer was washed with 5×100 ml of brine, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 2.98 g (39%) of the title compound as a white solid. MS-ESI: 396 (M+1).

Step 8: 1-(Difluoromethyl)-4-fluoro-1H-pyrazole-3-sulfonamide

To a stirred solution of N,N-dibenzyl-1-(difluoromethyl)-4-fluoro-1H-pyrazole-3-sulfonamide (2.97 g, 7.5 mmol) in DCM (30 mL) was added cc.H₂SO₄ (98% wt., 30 mL) dropwise at 0° C. The reaction mixture was stirred for 90 min at RT. The reaction mixture was quenched with 20 mL of water/ice. The pH value of the solution was adjusted to 7 with NaOH (5 M). The mixture was extracted with EtOAc (3×100 mL). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (15:1). This resulted in 1.31 g (81%) of the title compound as a white solid. MS-ESI: 214 (M−1).

Steps 9-10 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 213 from compound 810″. MS-ESI: 329 (M+1).

Intermediate 214

Tert-butyl 2-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)-4-(difluoromethyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate Step 1: 4-(Difluoromethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

To a stirred solution of 2-(thiophen-2-yl)ethan-1-amine (5.00 g, 39.3 mmol) in HCl (6 M, 40 mL) and water (40 mL) was added 1-ethoxy-2,2-difluoroethan-1-ol (5.45 g, 43.2 mmol) dropwise at RT. The reaction mixture was stirred for 12 h at RT and then diluted with 30 mL of water. The pH value of the solution was adjusted to 7 with NaOH (2 M). The resulting solution was extracted with 3×200 mL of EtOAc; the combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. This resulted in 3 g (40.3%) of the title compound as yellow oil. MS-ESI: 190 (M+1).

Step 2: Tert-butyl 4-(difluoromethyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate

To a stirred solution of 4-(difluoromethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (2.00 g, 10.6 mmol) in DCM (20 mL) was added TEA (2.14 g, 21.2 mmol) at RT, followed by the addition of (Boc)₂O (3.46 g, 15.9 mmol) in 10 mL DCM dropwise at RT. The resulting solution was stirred for 2 h at RT. The reaction was quenched with water 30 mL, and then extracted with EtOAc (3×50 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:10). This resulted in 2.20 g (71.9%) of the title compound as yellow oil. MS-ESI: 290 (M+1).

Step 3: Tert-butyl 4-(difluoromethyl)-2-sulfamoyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate

To a stirred solution of tert-butyl 4-(difluoromethyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (2.20 g, 7.60 mmol) in THF (20 mL) under nitrogen was added n-BuLi (2.5 M in hexane, 6.1 mL, 15.2 mmol) dropwise at −78° C. and stirred for 30 min at −78° C. To the above solution was bubbled SO₂ (g) for 15 min at −50° C. The reaction mixture was stirred for 1 h at RT, and then concentrated under vacuum. To the above residue was added DCM (20 mL), followed by NCS (1.52 g, 11.4 mmol) in small portions at 0° C. The reaction mixture was stirred for 1 h, and then NH₃ (g) was bubbled for 15 min at 0° C. The resulting mixture was further stirred for 2 h at RT. The reaction was quenched with water (50 mL) and extracted with DCM (3×100 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD, 30*150 mm, 5 um; mobile phase, Water (10 mM NH₄HCO₃+0.1% NH₃.H₂O) and ACN (35% to 40% Phase B over 7 min); Detector, UV 254 nm. This resulted in 500 mg (19.6%) of the title compound as a yellow solid. MS-ESI: 369 (M+1).

Steps 4-5 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 214 from compound 815″. MS-ESI: 482 (M+1).

Step 6: (S) and (R) tert-butyl 4-(difluoromethyl)-2-sulfamoyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate

Compound 815″ (120 mg) was resolved by chiral prep-HPLC using the following conditions: Column CHIRALPAK IA, 3*25 cm, 5 um; Mobile Phase A: Hex (8 mM NH₃ ⁻MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL/min; Gradient: 30% B to 30% B over 12 min; 254/220 nm; RT1: 7.85 min (Compound 815F″); RT2: 9.3 min (Compound 815S″). This resulted in 25.5 mg of Compound 815F″ and 27.0 mg of Compound 815S″; both as white solid. MS-ESI: 369 (M+1). The stereochemistry assignments of 815F″ and 815F″ are arbitrary.

TABLE 74 The intermediates in the following table were prepared using the similar procedures for converting compound 815″ to Intermediate 214 shown in Scheme 157 starting from 815F″ and 815S″. Exact Intermediate Mass # Structure IUPAC Name [M + H]⁺ Intermediate 214F

(S) or (R) tert-butyl 2-(N′-(tert- butyldimethylsilyl)sulfamidimidoyl)-4-(difluoromethyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate 482 Intermediate 214S

(R) or (S) tert-butyl 2-(N′-(tert- butyldimethylsilyl)sulfamidimidoyl)-4-(difluoromethyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate 482

Intermediate 215

Tert-butyl ((5-(N-(tert-butyldimethylsilyl)sulfamidimidoyl)-4-fluorothiophen-3-yl)methyl)(methyl)carbamate Step 1: 2-Chlorothiophene-3-carbonyl chloride

To a stirred solution of 2-chlorothiophene-3-carboxylic acid (5.00 g, 30.9 mmol) in DCM (300 mL) under nitrogen was added SOCl₂ (12.3 g, 104 mmol) dropwise at 0° C. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated under vacuum. This resulted in 5.00 g (crude) of the title compound as a yellow solid.

Step 2: 2-Chloro-N-methylthiophene-3-carboxamide

To a stirred solution of methanamine (2 M in THF, 150 mL, 300 mmol) under nitrogen was added 2-chlorothiophene-3-carbonyl chloride (5.00 g, crude from last step) in THF (10 mL) dropwise at 0° C. The resulting solution was stirred for 16 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in 3 g (55.6% over 2 steps) of the title compound as a white solid. MS-ESI: 176/178 (M+1).

Step 3: 1-(2-Chlorothiophen-3-yl)-N-methylmethanamine

To a stirred solution of 2-chloro-N-methylthiophene-3-carboxamide (3.00 g, 17.1 mmol) in THF (150 mL) under nitrogen was added BH₃-THF (1 M, 34.2 mL, 34.2 mmol) dropwise at 0° C. The resulting solution was stirred for 16 h at RT, then quenched with 10 mL of MeOH. The resulting mixture was concentrated. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in 2.0 g (72.5%) of the title compound as a white solid. MS-ESI: 162/164 (M+1).

Step 4: Tert-butyl ((2-chlorothiophen-3-yl)methyl)(methyl)carbamate

To a stirred solution of 1-(2-chlorothiophen-3-yl)-N-methylmethanamine (2.00 g, 12.4 mmol) in dioxane (100 mL) and water (10 mL) under nitrogen was added NaHCO₃ (3.12 g, 37.1 mmol) in portions at RT, followed by the addition of (Boc)₂O (4.05 g, 18.6 mmol) in dioxane (10 mL) dropwise at RT. The resulting solution was stirred for 16 h at RT. The resulting mixture was diluted with 50 ml of water, and extracted with 3×50 mL of DCM. The combined organic layers were dried over anhydrous Na₂SO₄. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in 2.5 g (77.2%) of the title compound as a white solid. MS-ESI: 262/264 (M+1).

Step 5: Tert-butyl ((2-chloro-5-(chlorosulfonyl)thiophen-3-yl)methyl)(methyl)carbamate

To a stirred solution of tert-butyl ((2-chlorothiophen-3-yl)methyl)(methyl)carbamate (2.50 g, 9.58 mmol) in THF (100 mL) under nitrogen was added n-BuLi (2.5 M in hexane, 9.60 mL, 24.0 mmol) dropwise at −78° C., the resulting solution was stirred for 1 h at −78° C. To the above solution was bubbled SO₂ (g) at −50° C. for 15 min. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated under vacuum. To the above residue was added DCM (50 mL), followed was added NCS (2.55 g, 19.2 mmol) in small portions at 0° C. The resulting mixture was stirred for 2 h at RT, then concentrated under vacuum. This resulted in 3.00 g (crude) of the title compound as a yellow solid. This compound was monitored by LC-MS after adding 7 M MeOH/NH₃to an aliquot of the reaction mixture, MS-ESI: 341/343 (M+1).

Step 6: Tert-butyl ((5-(N-(tert-butyl)sulfamoyl)-2-chlorothiophen-3-yl)methyl)(methyl)carbamate

To a stirred solution of tert-butyl ((2-chloro-5-(chlorosulfonyl)thiophen-3-yl)methyl)(methyl)carbamate (3.00 g, crude from last step) in DCM (100 mL) under nitrogen was added t-BuNH₂ (1.02 g, 13.8 mmol) dropwise at 0° C. The resulting solution was stirred for 16 h at RT. The resulting mixture was diluted with 100 mL of water and extracted with 3×100 mL of DCM. The combined organic layers were dried over anhydrous Na₂SO₄. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in 1.80 g (45.3% over 2 steps) of the title compound as a white solid. MS-ESI: 397/399 (M+1).

Step 7: Tert-butyl ((5-(N-(tert-butyl)sulfamoyl)-2-chloro-4-fluorothiophen-3-yl)methyl)(methyl)carbamate

To a stirred solution of tert-butyl ((5-(N-(tert-butyl)sulfamoyl)-2-chlorothiophen-3-yl)methyl)(methyl)-carbamate (1.80 g, 4.55 mmol) in THF (100 mL) under nitrogen was added n-BuLi (2.5 M in hexane, 3.64 mL, 9.10 mmol) dropwise at −78° C. The resulting solution was stirred for 1 h at −78° C. NFSI (2.87 g, 9.10 mmol) in THF (15 mL) was added dropwise at −78° C. under nitrogen. The resulting solution was stirred for 16 h at RT. The reaction mixture was quenched with 20 mL of water, extracted with 3×100 mL of EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 1.2 g (63.8%) of the title compound as a white solid. MS-ESI: 415/417 (M+1).

Step 8: Tert-butyl ((5-(N-(tert-butyl)sulfamoyl)-4-fluorothiophen-3-yl)methyl)(methyl)carbamate

To a stirred solution of tert-butyl ((5-(N-(tert-butyl)sulfamoyl)-2-chloro-4-fluorothiophen-3-yl)methyl)-(methyl)carbamate (1.2 g, 2.90 mmol) in MeOH (100 mL) under nitrogen was added Pd/C (10% wt., 240 mg) in portions at RT. The flask was evacuated and flushed with hydrogen 3 times. The resulting solution was stirred 16 h at RT under hydrogen with a balloon. The Pd/C catalysts were filtered out, the filtrate was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 700 mg (63.6%) of the title compound as a white solid. MS-ESI: 381 (M+1).

Step 9: 3-Fluoro-4-((methylamino)methyl)thiophene-2-sulfonamide

To a stirred solution of tert-butyl ((5-(N-(tert-butyl)sulfamoyl)-4-fluorothiophen-3-yl)methyl)(methyl)-carbamate (700 mg, 1.84 mmol) in DCM (10 mL) was added BCl₃ (1M in DCM, 5 mL, 5 mmol) dropwise at 0° C. The resulting solution was stirred for 16 h at RT. The reaction was then quenched by the addition of 10 mL of MeOH and concentrated under vacuum. This resulted in 450 mg (crude) of the title compound as yellow oil which was used in next step without further purification. MS-ESI: 225 (M+1).

Step 10: Tert-butyl ((4-fluoro-5-sulfamoylthiophen-3-yl)methyl)(methyl)carbamate

To a stirred solution of 3-fluoro-4-((methylamino)methyl)thiophene-2-sulfonamide (450 mg, crude from last step) in DCM (10 mL) was added TEA (362 mg, 3.58 mmol), followed by (Boc)₂O (781 mg, 3.58 mmol) in DCM (5 mL) dropwise at RT. The resulting solution was stirred for 16 h at RT. The resulting solution was extracted with 3×100 mL of EtOAc and the organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was purified by Prep-TLC (PE/EtOAc 1:1). This resulted in 500 mg (83.7% over 2 steps) of the title compound as yellow oil. MS-ESI: 325 (M+1).

Steps 11-12 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 215 from compound 827″. MS-ESI: 438 (M+1).

Intermediate 216

Tert-butyl (2-(N-(tert-butyldimethylsilyl)sulfamidimidoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)(methyl)carbamate Step 1: Ethyl (E)-4-(thiophen-3-yl)but-2-enoate

To a stirred solution of 2-(thiophen-3-yl)acetaldehyde (5.00 g, 39.7 mmol) in THF (100 mL) under nitrogen was added ethyl 2-(triphenyl-λ⁵-phosphaneylidene)acetate (13.8 g, 39.7 mmol) in THF (10 mL) dropwise at 0° C. The resulting solution was stirred for 3 h at RT. The resulting solution was extracted with 5×100 mL of EtOAc and the organic layers combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:4). This resulted in 4.25 g (54.6%) of the title compound as yellow oil. GC-MS-EI: 196 (M).

Step 2: Ethyl 4-(thiophen-3-yl)butanoate

To a stirred solution of ethyl (E)-4-(thiophen-3-yl)but-2-enoate (3.00 g, 15.3 mmol) in MeOH (50 mL) under nitrogen was added Pd/C (10% wt., 240 mg) in portions at RT. The flask was evacuated and flushed with hydrogen 3 times. The resulting solution was stirred 16 h at RT under hydrogen with a balloon. The Pd/C catalysts were filtered out, the filtrate was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:4). This resulted in 2.15 g (71.0%) of the title compound as yellow oil. GC-MS-EI: 198 (M).

Step 3: 4-(Thiophen-3-yl)butanoic acid

To a stirred solution of ethyl 4-(thiophen-3-yl)butanoate (5.00 g, 25.3 mmol) in MeOH (50 mL) was added aq. NaOH (4 M, 30 mL) dropwise at 0° C. The resulting mixture was stirred for 16 h at RT. The pH value of the mixture was adjusted to 5 with HCl (6 M). The mixture was extracted with EtOAc (3×300 mL). The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in (4.08 g, 95%) of the title compound as yellow oil. MS-ESI: 169 (M−1).

Step 4: 4-(Thiophen-3-yl)butanoyl chloride

To a stirred solution of 4-(thiophen-3-yl)butanoic acid (4.70 g, 27.6 mmol) in DCM (60 mL) and DMF (cat., 0.1 mL) under nitrogen was added oxalyl chloride (6.96 g, 55.2 mmol) dropwise at 0° C. The resulting mixture was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The crude product was used in next step without further purification. This compound was monitored by LC-MS after adding 7M MeOH/NH₃to an aliquot of the reaction mixture MS-ESI: 170 (M+1).

Step 5: 5,6-Dihydrobenzo[b]thiophen-7(4H)-one

To a stirred solution of 4-(thiophen-3-yl)butanoyl chloride (6.00 g, 31.9 mmol) in DCM (100 mL) under nitrogen was added anhydrous AlCl₃ (8.48 g, 64.2 mmol) in portions at 0° C. The resulting solution was stirred for 2 h at RT, then quenched with 300 mL of water/ice. The resulting solution was extracted with 3×300 mL of DCM and the organic layers were combined and concentrated under vacuum. This resulted in 4.2 g (86.6% over 2 steps) of the title compound as brown oil. MS-ESI: 153 (M+1).

Step 6: Methyl 7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-6-carboxylate

To a stirred solution of 5,6-dihydrobenzo[b]thiophen-7(4H)-one (2.80 g, 18.4 mmol) in DMF (20 mL) under nitrogen was added NaH (60% wt. dispersion in mineral oil, 1.68 g, 42.0 mmol) in portions at 0° C. The resulting solution was stirred for 30 min at 10° C., then dimethyl carbonate (9.94 g, 110 mmol) was added dropwise at 0° C. The resulting solution was stirred for 3 h at RT. The reaction was quenched with 10 mL of water. The resulting solution was extracted with 3×20 mL of EtOAc and the organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 3.3 g (85.3%) of the title compound as yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.06 (d, J=5.0 Hz, 1H), 7.17 (d, J=5.0 Hz, 1H), 3.81 (dd, J=8.8, 6.3 Hz, 1H), 3.69 (s, 3H), 3.02-2.85 (m, 2H), 2.40-2.25 (m, 2H).

Step 7: Methyl 7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thiophene-6-carboxylate

To a stirred solution of methyl 7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-6-carboxylate (5.00 g, 23.8 mmol) in THF (30 mL) and MeOH (20 mL) was added NaBH₄ (0.90 g, 23.7 mmol) in portions at 0° C. The resulting solution was stirred for 3 h at RT. The reaction mixture was quenched with 10 mL of water, organic solvent was removed under vacuum, then the residue was extracted with EtOAc (3×20 mL). The organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (3:7). This resulted in 1.8 g (35.7%) of the title compound as yellow oil. MS-ESI: 213 (M+1).

Step 8: Methyl 4,5,6,7-tetrahydrobenzo[b]thiophene-6-carboxylate

To a stirred solution of methyl 7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thiophene-6-carboxylate (1.40 g, 6.60 mmol) in DCM (40 mL) was added Et₃SiH (1.53 g, 13.2 mmol) and BF₃-Et₂O (47% wt. in Et₂O, 3.99 g, 13.2 mmol) dropwise at 0° C. The resulting solution was stirred for 16 h at 0° C. and then quenched with sat. NaHCO₃ (10 mL) and extracted with EtOAc (3×30 mL). The organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (30:70). This resulted in 1.2 g (92.7%) of the title compound as nearly colorless oil. MS-ESI: 197 (M+1).

Step 9: 4,5,6,7-Tetrahydrobenzo[b]thiophene-6-carboxylic acid

To a stirred solution of methyl 4,5,6,7-tetrahydrobenzo[b]thiophene-6-carboxylate (1.20 g, 6.12 mmol) in MeOH (50 mL) was added NaOH (4 M, 10 mL, 40 mmol) dropwise at RT. The resulting solution was stirred for 1 h at RT. The pH value of the mixture was adjusted to 6 with HCl (6 M) and extracted with 3×80 mL of EtOAc. The organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under vacuum. This resulted in 1.10 g (98.7%) of the title compound as brown oil. MS-ESI: 181 (M−1).

Step 10: Tert-butyl (4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)carbamate

To a stirred solution of 4,5,6,7-tetrahydrobenzo[b]thiophene-6-carboxylic acid (500 mg, 2.75 mmol) in toluene (20 mL) under nitrogen was added TEA (306 mg, 3.03 mmol) and t-BuOH (407 mg, 5.50 mmol) at RT. DPPA (831 mg, 3.02 mmol) in toluene (5 mL) was added dropwise at RT. The resulting solution was stirred for 16 h at 90° C. The reaction mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (5:95). This resulted in 540 mg (77.7%) of the title compound as yellow oil. MS-ESI: 254 (M+1).

Step 11: Tert-butyl methyl(4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)carbamate

To a stirred solution of tert-butyl (4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)carbamate (1.00 g, 3.95 mmol) in THF (20 mL) under nitrogen was added NaH (60% wt. dispersion in mineral oil, 395 mg, 9.87 mmol) in portions at 0° C., followed by the addition of MeI (2.81 g, 19.8 mmol) dropwise at 0° C. The resulting solution was stirred for 16 h at RT. The reaction mixture was quenched with 5 mL of water. The resulting solution was further diluted with 30 mL of water and extracted with 3×80 mL of EtOAc. The organic layers were combined and concentrated under vacuum. This resulted in 1.02 g (96.6%) of the title compound as yellow oil. MS-ESI: 268 (M+1).

Steps 12-15 used similar procedures for converting compound 814″ to Intermediate 214 shown in Scheme 157 to afford Intermediate 216 from compound 840″. MS-ESI: 460 (M+1).

Intermediate 217

N′-(tert-butyldimethylsilyl)-5-(2,2-difluoroethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-sulfonimidamide Step 1: 5-(2,2-Difluoroethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

To a stirred solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (5.0 g, 28.5 mmol) in isopropyl alcohol (200 mL) was added K₂CO₃ (9.83 g, 71.3 mmol) in portions and 2,2-difluoroethyl trifluoromethanesulfonate (12.2 g, 57.0 mmol) dropwise at RT. The resulting solution was stirred for 3 h at 65° C. The reaction was quenched with 10 mL of water and extracted with 3×150 mL of DCM. The organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 2.7 g (46.7%) of the title compound as yellow oil. MS-ESI: 204 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 7.26 (d, J=5.1 Hz, 1H), 6.77 (d, J=5.1 Hz, 1H), 6.18 (tt, J=55.8, 4.3 Hz, 1H), 3.64-3.59 (m, 2H), 2.97-2.81 (m, 4H), 2.81-2.74 (m, 2H).

Steps 2-5 used similar procedures for converting compound 814″ to Intermediate 214 shown in Scheme 157 to afford Intermediate 217 from compound 845″. MS-ESI: 396 (M+1).

Compound 847″ ¹H NMR (300 MHz, DMSO-d₆) δ 7.58 (s, 2H), 7.24 (s, 1H), 6.19 (tt, J=55.8, 4.3 Hz, 1H), 3.64-3.59 (m, 2H), 3.03-2.78 (m, 6H).

Intermediate 218

N′-(tert-butyldimethylsilyl)-2-(7-hydroxy-1,13-diphenyl-2,5,9,12-tetraoxatridecan-7-yl)thiazole-5-sulfonimidamide Step 1: 1,13-Diphenyl-2,5,9,12-tetraoxatridecan-7-ol

To a stirred solution of 2-(benzyloxy)ethan-1-ol (26.0 mL, 183 mmol) under nitrogen was added Na (2.20 g, 95.7 mmol) at 100° C., followed by the addition of 2-(chloromethyl)oxirane (2.40 mL, 30.8 mmol) dropwise at 80° C. for 16 h. The reaction was quenched with MeOH (20 mL) at 0° C. The resulting mixture concentrated and diluted with 20 mL of water, then extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×20 mL), dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was purified by RP-HPLC using the following conditions: column, C18 silica gel; mobile phase, 10 mM NH₄HCO₃ in water and ACN (10% ACN to 60% gradient over 30 min); detector, UV 210 nm. This resulted in 5.60 g (50.5%) of the title compound as a dark yellow oil. ¹H NMR (300 MHz, DMSO-d₆) δ 7.48-7.12 (m, 10H), 4.75 (d, J=5.2 Hz, 1H), 4.48 (s, 4H), 3.80-3.65 (m, 1H), 3.60-3.50 (m, 8H), 3.46-3.28 (m, 4H).

Step 2: 1,13-Diphenyl-2,5,9,12-tetraoxatridecan-7-one

To a stirred solution of 1,13-diphenyl-2,5,9,12-tetraoxatridecan-7-ol (2.70 g, 7.50 mmol) in DCM (20 mL) was added NMO (1.76 g, 15.0 mmol) and TPAP (0.527 g, 1.50 mmol) dropwise at RT. The resulting solution was stirred for 3 h at RT. The reaction was quenched with water (20 mL) and then extracted with 3×20 mL of EtOAc. The organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was purified by RP-HPLC with the following conditions: column, C18 silica gel; mobile phase, 10 mM NH₃HCO₃ in water and ACN (5% ACN to 55% gradient over 30 min); detector, UV 220 nm. This resulted in 800 mg (29.8%) of the title compound as light yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.55-7.15 (m, 10H), 4.50 (s, 4H), 4.25 (s, 4H), 3.65-3.50 (m, 8H).

Step 3: 1,13-Diphenyl-7-(thiazol-2-yl)-2,5,9,12-tetraoxatridecan-7-ol

To a stirred solution of 2-bromothiazole (3.00 g, 18.3 mmol) in THF (30 mL) under nitrogen was added t-BuLi (1.3 M in n-pentane, 15.4 mL, 20.1 mmol) dropwise at −78° C., followed by the addition of 1,13-diphenyl-2,5,9,12-tetraoxatridecan-7-one (6.55 g, 18.3 mmol) dropwise at −78° C. The resulting mixture was stirred for 3 h at −78° C. The reaction was quenched with water (10 mL). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (3×20 mL), dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was eluted from silica gel column with PE/EtOAC (1:1) to afford 3.7 g (46.7%) the title compound as a light yellow oil. MS-ESI: 444 (M+1). ¹H NMR (300 MHz, DMSO-d₆) δ 7.72 (d, J=3.2 Hz, 1H), 7.61 (d, J=3.2 Hz, 1H), 7.38-7.20 (m, 10H), 5.96 (s, 1H), 4.43 (s, 4H), 3.85-3.69 (m, 4H), 3.62-3.39 (m, 8H).

Steps 4-7 used similar procedures for converting compound 814″ to Intermediate 214 shown in Scheme 157 to afford Intermediate 218 from compound 852″. MS-ESI: 636 (M+1).

Intermediate 219

5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine Step 1: N-(2,3-dihydro-1H-inden-4-yl)pivalamide

To a stirred solution of 2,3-dihydro-1H-inden-4-amine (7.00 g, 52.6 mmol) in THF (200 mL) was added TEA (7.98 g, 78.8 mmol) at RT. This was followed by the addition of pivaloyl chloride (7.60 g, 63.1 mmol) dropwise by syringe at RT. The reaction mixture was stirred at RT for 6 h. The reaction was quenched with water (200 mL). The resulting solution was extracted with 3×200 mL of DCM, the organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The reaction mixture was eluted from silica gel with PE/EtOAC (1:10). This result in 21 g (95.0%) of the title compound as a brown solid. MS-ESI: 218 (M+1)

Step 2: N-(5-bromo-2,3-dihydro-1H-inden-4-yl)pivalamide

To a stirred solution of N-(2,3-dihydro-1H-inden-4-yl)pivalamide (13.5 g, 62.1 mmol) in toluene (200 mL) was added Pd(OAc)₂ (0.70 g, 3.11 mmol), NBS (13.3 g, 74.5 mmol) and TsOH (5.33 g, 31.0 mmol) in portions at RT. The resulting mixture was stirred under air for 16 h at RT. The reaction was then quenched with aq. NaHCO₃ (sat., 20 mL). The resulting solution was extracted with 3×20 mL of EtOAc. The organic layers were combined, washed with brine (2×20 mL), dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:20). This resulted in 12.0 g (65.0%) of the title compound as a light yellow solid. MS-ESI: 296/298 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 9.09 (s, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 2.87 (t, J=7.4 Hz, 2H), 2.70 (t, J=7.5 Hz, 2H), 2.08-1.92 (m, 2H), 1.23 (s, 9H).

Step 3: 5-Bromo-2,3-dihydro-1H-inden-4-amine

To a stirred solution of N-(5-bromo-2,3-dihydro-1H-inden-4-yl)pivalamide (2.00 g, 6.75 mmol) in MeOH (10 mL) was added H₂SO₄ (conc., 10 mL) dropwise at 0° C. The resulting solution was stirred for 16 h at 100° C. The reaction mixture was cooled to 0° C. and added dropwise to 100 mL of water carefully. The pH value of the mixture was adjusted to 14 with NaOH (2 M). The resulting mixture was extracted with 3×150 mL of EtOAc, the organic layers were combined and dried over anhydrous Na₂SO₄. The residue was eluted from silica gel with EtOAc/PE (1:15). This resulted in 1.16 g (81.0%) of the title compound as a yellow solid. LCMS-ESI: 212 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 7.11 (d, J=7.9 Hz, 1H), 6.41 (d, J=7.9 Hz, 1H), 4.98 (s, 2H), 2.76 (t, J=7.5 Hz, 2H), 2.70 (t, J=7.4 Hz, 2H), 2.10-1.90 (m, 2H).

Step 4: 5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

To a stirred solution of 5-bromo-2,3-dihydro-1H-inden-4-amine (1.50 g, 7.07 mmol) in dioxane (30 mL) and water (6 mL) was added K₂CO₃ (3.23 g, 23.3 mmol) and (2-methoxypyridin-4-yl)boronic acid (1.62 g, 10.6 mmol) in portions at RT. The mixture was degassed with nitrogen for 15 min before Pd(dppf)Cl₂ (517 mg, 0.71 mmol) was added. The resulting mixture was stirred for 2 h at 80° C. under nitrogen. The resulting mixture was diluted with 150 mL of water and extracted with 3×120 mL of EtOAc, the organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:10). This resulted in 1.37 g (62.9%) of the title compound as a light yellow solid. LCMS-ESI: 241 (M+1).

Intermediate 220

4-(4-Isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine

To a stirred solution of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (165 mg, 0.68 mmol) in THF (5 mL) under nitrogen was added BTC (102 mg, 0.34 mmol) in portions at RT. The resulting solution was stirred for 2 h at 80° C. The resulting mixture was concentrated under vacuum. The crude product was used for next step without purification. This compound was monitored by LC-MS after adding MeOH to an aliquot of the reaction mixture, MS-ESI: 299 (M+1)

Schemes of Sulfonimidamide and Aniline Intermediates: Schemes 164-175 illustrate the preparations of sulfonimidamide and aniline intermediates.

Intermediate 221

N′-(tert-butyldimethylsilyl)-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide Step 1: N-(tert-butyl)-5-chlorothiophene-2-sulfonamide

To a stirred solution of t-BuNH₂ (20.2 g, 276 mmol) in DCM (180 mL) under nitrogen was added TEA (42.0 g, 415 mmol), followed by the addition of 5-chlorothiophene-2-sulfonyl chloride (10.0 g, 46.3 mmol) in DCM (20 mL) dropwise at 0° C. The resulting solution was stirred for 16 h at 35° C. The reaction was quenched with water/ice (200 mL) and extracted with DCM (2×200 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:10). This resulted in 11.0 g (93.9%) of the title compound as a yellow solid. MS-ESI: 252/254 (M−1). ¹H NMR (400 MHz, DMSO-d₆) δ 7.90 (s, 1H), 7.46 (d, J=4.0 Hz, 1H), 7.21 (d, J=4.1 Hz, 1H), 1.17 (s, 9H).

Step 2: N-(tert-butyl)-5-chloro-3-fluorothiophene-2-sulfonamide

To a stirred solution of N-(tert-butyl)-5-chlorothiophene-2-sulfonamide (11.0 g, 43.5 mmol) in THF (200 mL) under nitrogen was added n-BuLi (2.5 M in hexane, 52.4 mL, 131 mmol) dropwise at −78° C. The resulting solution was stirred at −78° C. for 1 h. To the above solution was added NFSI (41.6 g, 131 mmol) in THF (100 mL) dropwise at −78° C. The resulting solution was slowly warmed to RT, and stirred at RT for another 1 h. The reaction mixture was then quenched with water/ice (250 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:20). This resulted in 6.2 g (43.3%) of the title compound as a yellow solid. MS-ESI: 270/272 (M−1).

Step 3: N-(tert-butyl)-5-chloro-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

To a stirred solution of N-(tert-butyl)-5-chloro-3-fluorothiophene-2-sulfonamide (6.2 g, 22.8 mmol) in THF (200 mL) under nitrogen was added n-BuLi (2.5 M in hexane, 91.2 mL, 228 mmol) dropwise at −78° C. The resulting solution was stirred for 50 min at −78° C. To this was added acetone (53.0 g, 913 mmol) dropwise with stirring at −78° C. The resulting solution was stirred for additional 1.5 h at −60° C. The reaction was then quenched with water/ice (200 mL) and extracted with EtOAc (2×300 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:5). This resulted in 4.4 g (65.4%) of the title compound as yellow oil. MS-ESI: 328/330 (M−1).

Step 4: N-(tert-butyl)-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

To a stirred solution of N-(tert-butyl)-5-chloro-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (4.3 g, 13.1 mmol) in MeOH (80 mL) under nitrogen was added Pd/C (10% wt, 470 mg) in portions at RT. The flask was evacuated and refilled with hydrogen three times. The resulting mixture was stirred for 16 h at RT under hydrogen with a balloon. The solids were filtered out and the filtrate was concentrated under vacuum. This resulted in 3.88 g (crude) of the title compound as a white solid. MS-ESI: 294 (M−1).

Step 5: 3-Fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

To a stirred solution of N-(tert-butyl)-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (3.88 g, 13.1 mmol) in DCM (78 mL) under nitrogen was added BCl₃ (1 M in DCM, 39 mL, 39 mmol) dropwise at 0° C. The resulting solution was stirred for 3 h at RT. The reaction was then quenched with water/ice (80 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (2:3). This resulted in 1.9 g (60.7% over 2 steps) of the title compound as yellow oil. MS-ESI: 238 (M−1).

Step 6: N-(tert-butyldimethylsilyl)-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

To a stirred solution of 3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (1.89 g, 7.91 mmol) in THF (40 mL) under nitrogen was added NaH (60% wt., 630 mg, 15.9 mmol) in portions at 0° C., followed by the addition of TBSCl (2.39 g, 15.9 mmol) in THF (5 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was quenched with water/ice (50 mL). The resulting solution was extracted with EtOAc (2×50 mL). The organic layers were combined and dried over anhydrous Na₂SO₄. The resulting solution was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:3). This resulted in 2.1 g (75.2%) of the title compound as a white solid. MS-ESI: 352 (M−1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (s, 1H), 7.56 (d, J=5.1 Hz, 1H), 5.38 (s, 1H), 1.43 (s, 6H), 0.89 (s, 9H), 0.16 (s, 6H).

Step 7: N′-(tert-butyldimethylsilyl)-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide

To a stirred solution of PPh₃Cl₂ (1.41 g, 4.24 mmol) in CHCl₃ (15 mL) under nitrogen was added DIEA (1.83 g, 14.1 mmol) dropwise at 0° C. The resulting solution was stirred for 15 min at 0° C. To the above solution was added N-(tert-butyldimethylsilyl)-2-(difluoromethyl)thiazole-5-sulfonamide (1.0 g, 2.83 mmol) in CHCl₃ (10 mL) dropwise at 0° C. The resulting solution was stirred for 2 h at 0° C. NH₃ (g) was bubbled into the reaction solution for 10 min at 0° C. Then the solution was stirred for another 30 min at RT. The solids were filtered out, the filtrate was diluted with water (20 mL). The resulting solution was extracted with DCM (3×20 mL). The organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in 800 mg (80.1%) of the title compound as an off-white solid. MS-ESI: 353 (M+1).

Intermediate 222

N′-(tert-butyldimethylsilyl)-2-fluoro-5-(2-hydroxypropan-2-yl)benzenesulfonimidamide Step 1: Ethyl 4-fluoro-3-sulfamoylbenzoate

To a stirred solution of ethyl 3-amino-4-fluorobenzoate (500 mg, 2.73 mmol) in HCl (6 M, 5 mL) was added NaNO₂ (226 mg, 3.28 mmol) in water (0.5 mL) dropwise at 0° C. The resulting solution was stirred for 30 min at 0° C., the mixture was assigned as A. SO₂ (g) was bubbled in AcOH (10 mL) for 5 min at 0° C., then to the solution was added CuCl (272 mg, 2.73 mmol) at 0° C., this mixture was assigned as B. Mixture A was added to mixture B dropwise at 0° C. The resulting mixture was stirred for 30 min at RT. The reaction mixture diluted with water (20 mL), then extracted with DCM (3×30 mL). The organic layers were combined and dried over anhydrous Na₂SO₄. To the above solution was bubbled NH₃ at 0° C. for 3 min. The resulting mixture was stirred for 30 min at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:3). This resulted in 500 mg (74.1%) of the title compound as a white solid. MS-ESI: 246 (M−1).

Step 2: 2-Fluoro-5-(2-hydroxypropan-2-yl)benzenesulfonamide

To a stirred solution of ethyl 4-fluoro-3-sulfamoylbenzoate (500 mg, 2.02 mmol) in THF (40 mL) was added MeMgBr (3 M in THF, 5.4 mL, 16.2 mmol) dropwise at 0° C. The resulting solution was stirred for 16 h at RT. The resulting mixture was quenched with 30 mL of saturated NH₄Cl (aq.), extracted with 3×50 mL of EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄. The resulting solution was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:3). This resulted in 420 mg (89.2%) of the title compound as a white solid. MS-ESI: 232 (M−1).

Steps 3-4 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 222 from compound 869″. MS-ESI: 347 (M+1).

Intermediate 223

N′-(tert-butyldimethylsilyl)-3,5-bis(2-hydroxypropan-2-yl)benzenesulfonimidamide

Steps 1-2 used similar procedures for converting compound 867″ to compound 868″ shown in Scheme 165 to afford compound 873″ from compound 871″. MS-ESI: 272 (M−1).

Step 3: 3,5-Bis(2-hydroxypropan-2-yl)benzenesulfonamide

To a stirred solution of dimethyl 5-sulfamoylisophthalate (5 g, 18.3 mmol) in THE (100 mL) was added MeMgBr (3 M in THF, 120 mL, 360 mmol) dropwise at 0° C. The resulting mixture was stirred for 48 h at RT. The reaction mixture was quenched with 200 mL of sat. NH₄Cl (aq.), then extracted with 3×200 mL of EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄. The resulting solution was concentrated under vacuum. The crude product was purified by reverse column using the following conditions: Column, C₁₈ silica gel; mobile phase, ACN and water: increasing to ACN/water from 0/100 to 90/10 over 30 min; Detector, UV 254 nm. This resulted in 2.5 g (50.0%) of the title compound as a white solid. MS-ESI: 274 (M+1).

Steps 4-5 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 223 from compound 874″. MS-ESI: 387 (M+1).

Intermediate 224

N′-(tert-butyldimethylsilyl)-3-cyano-5-(2-hydroxypropan-2-yl)benzenesulfonimidamide

Steps 1-2 used similar procedures for converting compound 867″ to compound 869″ shown in Scheme 165 to afford compound 879″ from compound 876″. MS-ESI: 292/294 (M−1).

Step 4: 3-Cyano-5-(2-hydroxypropan-2-yl)benzenesulfonamide

To a stirred solution of 3-bromo-5-(2-hydroxypropan-2-yl)benzenesulfonamide (294 mg, 1.00 mmol) in DMF (5 mL) under nitrogen was added Zn(CN)₂ (232 mg, 2.00 mmol) and Pd(PPh₃)₄ (231 mg, 0.20 mmol). The resulting mixture was stirred for 5 h at 80° C. The reaction mixture was quenched with 20 mL of water, and then extracted with 3×20 ml of EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄. The resulting solution was concentrated under vacuum. The residue was eluted from a silica gel with EtOAc/PE (2:1). This resulted in 150 mg (62.5%) of the title compound as a yellow solid. MS-ESI: 239/240 (M−1).

Steps 5-6 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 224 from compound 880″. MS-ESI: 354 (M+1).

Intermediate 225

N′-(tert-butyldimethylsilyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(2-hydroxypropan-2-yl)benzenesulfonimidamide

Steps 1-2 used similar procedures for converting compound 867″ to compound 868″ shown in Scheme 165 to afford compound 884″ from compound 882″. MS-ESI: 212 (M−1).

Step 3: 3-(Hydroxymethyl)-4-(2-hydroxypropan-2-yl)benzenesulfonamide

To a stirred mixture of 1-oxo-1,3-dihydroisobenzofuran-5-sulfonamide (1.3 g, 6.10 mmol) and LiCl (119 mg, 2.81 mmol) in THF (40 mL) under nitrogen was added MeMgBr (3 M in THF, 40.7 mL, 122 mmol) dropwise at 0° C. The resulting mixture was stirred for 16 h at RT. The reaction was quenched with 50 mL of sat. NH₄Cl (aq.) at 0° C. The resulting mixture was extracted with 3×100 mL of EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄. The resulting solution was concentrated under vacuum. This resulted in 1.1 g (73.6%) of the title compound as red oil. MS-ESI: 246 (M+1).

Step 4: 3-(((Tert-butyldimethylsilyl)oxy)methyl)-4-(2-hydroxypropan-2-yl)benzenesulfonamide

To a stirred solution of 3-(hydroxymethyl)-4-(2-hydroxypropan-2-yl)benzenesulfonamide (1.1 g, 4.49 mol) in DCM (40 mL) under nitrogen was added TEA (1.36 g, 13.5 mmol) and TBSCl (1.01 g, 6.74 mmol) at RT. The resulting mixture was stirred for 6 h at RT. The reaction mixture was quenched with 40 mL of water, extracted with 3×30 mL of DCM. The organic layers were combined and dried over anhydrous Na₂SO₄. The resulting solution was concentrated under vacuum. The residue was eluted from a silica gel column with DCM/MeOH (100:1). This resulted in 1.3 g (80.6%) of the title compound as an off-white solid. MS-ESI: 360 (M+1).

Steps 5-6 used similar procedures for converting compound 639″ to Intermediate 183 shown in Scheme 128 to afford Intermediate 225 from compound 886″. MS-ESI: 473 (M+1).

Intermediate 226

N′-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide Step 1: (2-Bromothiazol-4-yl)methanol

To a stirred solution of ethyl 2-bromothiazole-4-carboxylate (3.0 g, 12.8 mmol) in EtOH (30 mL) was added NaBH₄ (1.0 g, 25.4 mmol) in portions at 0° C. The resulting solution was stirred for 3 h at RT. The reaction was quenched with 100 mL of water at 0° C. Then extracted with 3×100 ml of EtOAc, the organic layers were combined and dried over anhydrous Na₂SO₄. The resulting solution was concentrated under vacuum. This resulted in 2 g (81.0%) of the title compound as yellow oil. MS-ESI: 194/196 (M+1).

Step 2: 2-Bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole

To a stirred solution of (2-bromothiazol-4-yl)methanol (2.0 g, 10.3 mmol) in THF (20 mL) under nitrogen was added NaH (60% wt., 1.2 g, 30.9 mmol) in portions at 0° C. After stirring for 15 minutes at RT, a solution of TBSCl (4.7 g, 30.9 mmol) in THF (5 mL) was added dropwise at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched with 50 mL of water. The resulting solution was extracted with 3×100 mL of EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from a silica gel column EtOAc/PE (1:30). This resulted in 2.5 g (79%) of the title compound as yellow oil. MS-ESI: 310/308 (M+1).

Step 3: 2-(4-((Tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)propan-2-ol

To a stirred mixture of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole (2.5 g, 8.14 mmol) in THF (30 mL) under nitrogen was added n-BuLi (2.5 M in hexane, 4.86 mL, 12.2 mmol) dropwise at −78° C. After stirring for 30 min at −78° C., to the above was added acetone (1.8 g, 32.4 mmol) dropwise at −78° C. The resulting mixture was stirred for 1 h at RT. The resulting mixture was quenched with 50 mL of water, extracted with 3×100 ml of EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄. The resulting solution was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:10). This resulted in 2 g (85.6%) of the title compound as yellow oil. MS-ESI: 288 (M+1).

Steps 4-7 used similar procedures for converting compound 665″ to Intermediate 188 shown in Scheme 133 to afford Intermediate 226 from compound 891″. MS-ESI: 480 (M+1).

Intermediate 227

3,5,6,7-Tetrahydro-2H-indeno[5,6-b]furan-8-amine Step 1: (Z)-3-(2,3-Dihydrobenzofuran-5-yl)acrylic acid

To a stirred solution of 2,3-dihydrobenzofuran-5-carbaldehyde (25 g, 169 mmol) in pyridine (200 mL) under nitrogen was added malonic acid (21.5 g, 203 mmol) and piperidine (1.4 g, 16.44 mmol). The resulting solution was stirred for 16 h at 100° C. The resulting mixture was cooled to RT, diluted with water (200 mL), and extracted with EtOAc (3×200 mL). The organic layers were combined and dried over anhydrous Na₂SO₄ then concentrated under vacuum. This resulted in 30 g (93.4%) of the title compound as a yellow solid. MS-ESI: 189 (M−1).

Step 2: 3-(2,3-Dihydrobenzofuran-5-yl)propanoic acid

To a stirred solution of (Z)-3-(2,3-dihydrobenzofuran-5-yl)acrylic acid (25 g, 132 mmol) in MeOH (200 mL) under nitrogen was added Pd/C (10% wt., 4 g). The flask was evacuated and refilled with hydrogen three times. The resulting solution was stirred for 16 h at RT under hydrogen with a balloon. The solids were filtered out and the filtrate was concentrated under vacuum. This resulted in 25 g (98.6%) of the title compound as a light yellow solid. MS-ESI: 191 (M−1).

Step 3: 3-(2,3-Dihydrobenzofuran-5-yl)propanoyl chloride

To a stirred solution of 3-(2,3-dihydrobenzofuran-5-yl)propanoic acid (20 g, 104 mmol) in DCM (200 mL) under nitrogen was added oxalyl chloride (13.21 g, 104 mmol). The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. This resulted in 20 g (crude) of the title compound as a light yellow liquid which was used for next step without further purification.

Step 4: 2,3,5,6-Tetrahydro-7H-indeno[5,6-b]furan-7-one

To a stirred solution of 3-(2,3-dihydrobenzofuran-5-yl)propanoyl chloride (crude from last step) in DCM (200 mL) under nitrogen was added AlCl₃ (12.7 g, 95.2 mmol) in portions at 0° C. The resulting solution was stirred for 2 h at 0° C. The reaction was quenched with 200 mL of water/ice, extracted with 3×200 mL of DCM. The organic layers were combined and dried over anhydrous Na₂SO₄. The resulting solution was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:3). This resulted in 10 g (54.6% over two steps) of the title compound as a yellow solid. MS-ESI: 175 (M+1).

Step 5: 8-Nitro-2,3,5,6-tetrahydro-7H-indeno[5,6-b]furan-7-one

To a stirred solution of 2,3,5,6-tetrahydro-7H-indeno[5,6-b]furan-7-one (5 g, 28.7 mmol) in conc. H₂SO₄ (20 mL) was added HNO₃ (1.99 g, 31.6 mmol) dropwise at 0° C. The resulting solution was stirred for 2 h at 0° C. The resulting solution was diluted with 200 mL of ice/water, extracted with 3×100 mL of DCM. The organic layers were combined and dried over anhydrous Na₂SO₄. The resulting mixture was concentrated under vacuum. This resulted in 5 g (79.6%) of the title compound as a light yellow solid. MS-ESI: 220 (M+1).

Step 6: 3,5,6,7-Tetrahydro-2H-indeno[5,6-b]furan-8-amine

To a stirred solution of 8-nitro-2,3,5,6-tetrahydro-7H-indeno[5,6-b]furan-7-one (5 g, 22.8 mmol) in MeOH (50 mL) was added methanesulfonic acid (675 mg, 7.0 mmol) and Pd(OH)₂/C (20% wt., 1 g). The flask was evacuated and refilled with hydrogen three times. The resulting solution was stirred for 16 h at RT under hydrogen with a balloon. The pH value of the solution was adjusted to 9 with 1M NaOH (aq.). The solids were filtered out and the filtrate was concentrated under vacuum. This resulted in 3.50 g (87.7%) of the title compound as a yellow solid. MS-ESI: 176 (M+1).

Intermediate 228

Tert-butyl (amino(2-(2-hydroxypropan-2-yl-1,1,1,3,3,3-d₆)thiazol-5-yl)(oxo)-λ⁶-sulfaneylidene)carbamate Step 1: (Methyl-d₃)magnesium iodide

To a stirred mixture of Mg turnings (10.0 g, 410 mmol) and iodine (10.0 mg, a small crystal) in Et₂O (1.3 L) under nitrogen was added CD3I (50 g, 345 mmol) in Et₂O (100 mL) dropwise at 0° C. The resulting mixture was stirred for 2 h at RT. This resulted in the title compound (crude in Et₂O, ˜0.25 M) as a grey solution which was used for next step without further purification.

Step 2: 2-(Thiazol-2-yl)propan-1,1,1,3,3,3-d₆-2-ol

To a stirred solution of (methyl-d₃)magnesium iodide (crude 0.25 M in Et₂O, 1.4 L, 350 mmol) under nitrogen was added methyl thiazole-2-carboxylate (10.7 g, 74.8 mmol) in THF (150 mL) dropwise at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was quenched with 200 mL of water at 0° C. Then extracted with 2×1 L of EtOAc, the organic layers were combined and dried over anhydrous Na₂SO₄. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:10). This resulted in 9 g (80.7%) of the title compound as a white solid. MS-ESI: 150 (M+1).

Steps 3-7 used similar procedures for converting compound 87 to Intermediate 28 shown in Scheme 16 to afford Intermediate 228 from compound 903″. MS-ESI: 328 (M+1).

Intermediate 229

N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-4-phenylthiophene-2-sulfonimidamide Step 1: Methyl 3-phenylthiophene-2-carboxylate

To a stirred solution of methyl 3-bromothiophene-2-carboxylate (3.0 g, 13.6 mmol) in dioxane (40 mL) and H₂O (13 mL) under nitrogen was added phenylboronic acid (1.99 g, 16.3 mmol), Na₂CO₃ (2.16 g, 20.4 mmol) and Pd(PPh₃)₄ (784 mg, 0.679 mmol). The resulting mixture was stirred for 5 h at 90° C. The reaction was diluted with 50 mL of water. Then extracted with 3×50 mL of EtOAc, the organic layers were combined and dried over anhydrous Na₂SO₄. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel column with EtOAc/PE (1/3). This resulted in 2.8 g (94.4%) of the title compound as a light yellow solid. MS-ESI: 219 (M+1).

Step 2: Methyl 3-phenyl-5-sulfamoylthiophene-2-carboxylate

To a stirred solution of methyl 3-phenylthiophene-2-carboxylate (2.8 g, 12.8 mmol) in CHCl₃ (30 mL) under nitrogen was added chlorosulfonic acid (3.0 g, 25.6 mmol) dropwise at 0° C. The solution was stirred for 2 h at RT, then PCl₅ (13.2 g, 64.0 mmol) was added in portions at 70° C. The resulting mixture was stirred for 3 h at 70° C. The reaction mixture was slowly poured into 100 mL of ice/water. Then extracted with 3×50 mL of DCM, the organic layer were combined and dried over anhydrous Na₂SO₄. The resulting solution was concentrated under vacuum. The residue was dissolved in THF (50 mL), then NH₃ (g) was bubbled for 5 min at 0° C. The resulting mixture was stirred for 1 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel column with EtOAc/PE (1/2). This resulted in 2.0 g (52.6%) of the title compound as a light yellow solid. MS-ESI: 296 (M−1).

Steps 3-5 used similar procedures for converting compound 868″ to Intermediate 222 shown in Scheme 165 to afford Intermediate 229 from compound 910″. MS-ESI: 411 (M+1).

Intermediate 230

N-(tert-butyldimethylsilyl)-4-(isopropyl(methyl)amino)benzenesulfonimidamide Step 1: 4-Bromo-N-isopropylaniline

To a stirred solution of 4-bromoaniline (7.6 g, 44.2 mmol) in EtOH (50 mL) and H₂O (50 mL) under nitrogen was added AcONa (10.9 g, 133 mmol), AcOH (40 mL) and acetone (12.8 g, 221 mmol) at 0° C. The resulting mixture was stirred for 30 min at RT. To the above mixture was added NaBH₄ (8.36 g, 221 mmol) in portions slowly at 0° C. The resulting mixture was stirred for 2 h at 0° C. The reaction was quenched with 50 mL of NaOH (2 M, aq.), extracted with 3×100 mL of EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄. The resulting solution was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in 9 g (95.6%) of the title compound as a yellow solid. MS-ESI: 214/216 (M+1).

Step 2: 4-Bromo-N-isopropyl-N-methylaniline

To a stirred solution of 4-bromo-N-isopropylaniline (9 g, 42.3 mmol) in DMF (100 mL) under nitrogen was added K₂CO₃ (11.7 g, 84.6 mmol), followed by the addition of MeI (30.1 g, 212 mmol) dropwise at 0° C. The resulting mixture was stirred for 16 h at 80° C. The reaction was quenched with 150 mL of water/ice, extracted with 3×100 mL of EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄. The resulting solution was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in 6.18 g (64.4%) of the title compound as a yellow oil. MS-ESI: 228/230 (M+1).

Steps 3-7 used similar procedures for converting compound 642″ to Intermediate 184 shown in Scheme 129 to afford Intermediate 230 from compound 915″. MS-ESI: 342 (M+1).

Intermediate 231

1,2,3,5,6,7-Hexahydrodicyclopenta[b,e]pyridin-8-amine

To a mixture of 2-aminocyclopent-1-ene-1-carbonitrile (5.4 g, 50 mmol) in DCE (125 mL) under nitrogen was added cyclopentanone (8.4 g, 100 mmol) at RT, followed by the addition of BF₃.Et₂O (47% wt., 100 mmol, 14.5 g) dropwise at 0° C. The resulting mixture was heat to 75° C. for 6 h. The reaction cooled to RT, then quenched with water/ice (100 mL), extracted with DCM (2×50 mL) to remove the impurities. The aqueous phase was collected and its pH value adjusted to 14 with NaOH (6 M). A solid was precipitated and collected by filtration. The filter cake was washed with water (150 mL) then dried under infra-red light. This resulted in 7.0 g of the title compound (80%) as a light yellow solid. MS-ESI: 175 (M+1).

Intermediate 232

3, 5-Diisopropylpyridin-4-amine Step 1: 3,5-Di(prop-1-en-2-yl)pyridin-4-amine

To a stirred solution of 3,5-dibromopyridin-4-amine (5.0 g, 20 mmol) in dioxane (150 mL) and water (15 mL) under nitrogen was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (10 g, 60 mmol), Cs₂CO₃ (19.6 g, 60 mmol) and Pd(dppf)Cl₂ (1.46 g, 2.0 mmol). The resulting solution was stirred for 15 h at 90° C. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel with EtOAc/PE (1:3). This resulted in 3.0 g (87%) of the title compound as light yellow oil. MS-ESI: 175 (M+1).

Step 2: 3,5-Diisopropylpyridin-4-amine

To a stirred solution of 3,5-di(prop-1-en-2-yl)pyridin-4-amine (3.0 g, 17.2 mmol) in MeOH (50 mL) under nitrogen was added Pd/C (wet.10% wt., 300 mg). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 16 h at RT under hydrogen with a balloon. The Pd/C catalysts were filtered out, the filtrate was concentrated under vacuum. This resulted in 2.8 g (91%) of the title compound as a light yellow solid. MS-ESI: 178 (M+1).

Reagent 1 Dichlorotriphenylphosphorane

This reagent was either purchased or prepared using the following procedure:

An oven dried 40 mL vial equipped with a stir bar was capped with a rubber septum and flushed with nitrogen. At room temperature, a solution of PPh₃ (0.85 g, 3.2 mmol) in anhydrous 1,2-dichloroethane (5 mL) was introduced via syringe. The reaction vessel was immersed in an ice/water bath and cooled for 5 min. A solution of hexachloroethane (0.76 g, 3.2 mmol) in anhydrous 1,2-dichloroethane (5 mL) was introduced dropwise via syringe. After the addition was complete the reaction mixture was stirred at the same temperature for an additional 5 min and then placed into a preheated block set at 80° C. Heating was continued for 4.5 h, at which time the reaction was assumed to be complete. The light golden clear solution was cooled to ambient temperature. The reagent thus prepared was transferred via syringe in subsequent reactions without any work up or purification. The total volume of the reaction mixture was 11 mL for the molar calculations for next steps. This solution containing PPh₃Cl₂ was stored under nitrogen at room temperature until used.

Reagent 2 Polymer-Bound dichlorotriphenylphosphorane

Polystyrene bound PPh₃ (0.32 g, 0.32 mmol) was suspended in anhydrous dichloroethane (6 mL) and shaked on a shaker for 5 mins. It was then filtered and the process was repeated again to swell the polymer. Filtered resin was suspended in anhydrous dichloroethane (6 mL) a third time and the whole suspension was transferred into an oven dried 40 mL vial with a stir bar via pipette. The vial was capped with a rubber septum and connected to a steady flow of nitrogen. The reaction vessel was immersed in an ice/water bath and cooled down for 10 min. A solution of hexachloroethane (0.076 g, 0.32 mmol) in anhydrous 1,2-dichloroethane (2 mL) was introduced drop wise via syringe. After the addition was complete the reaction mixture was placed in an already heated block set at 82° C. for 5 h. At this point the reaction is assumed to be completed. It was gradually brought to room temperature and used in the next step as is. This reagent was used at 1.5 equiv. with respect to sulfonamide in the next step.

SYNTHETIC EXAMPLES Example 1

Example 1 (181) N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide

Example 1 was synthesized according to the general method shown in Scheme 1, as illustrated below.

Examples 2 and 3

Examples 2 and 3 Examples 2 (181a) and 3 (181b) (S)- and (R)-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide

Examples 2 and 3 were prepared through chiral separation of Example 1 as illustrated below.

Step 1: N′-(tert-butyldimethylsilyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide

Into a 50-mL round-bottom flask was placed N′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide (200 mg, 0.6 mmol), THF (10 mL), NaH (60% wt, 48 mg, 1.2 mmol). This was followed by the addition of a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (120 mg, 0.6 mmol) in THF (1 mL) dropwise with stirring at RT. The resulting solution was stirred for 12 h at RT. The reaction was then quenched by the addition of 10 mL of NH₄Cl (sat.). The resulting solution was extracted with 3×10 mL of DCM and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:10 to 1:3). This resulted in 140 mg (43.8%) of the title compound as brown oil. MS-ESI: 532.0 (M−1).

Step 2: N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide

Into a 50-mL round-bottom flask was placed N′-(tert-butyldimethylsilyl)-N-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide (130 g, 0.2 mmol), THF (10 mL), and TBAF (300 mg, 0.5 mmol). The resulting solution was stirred for 2 h at RT and then concentrated under vacuum. The crude product was purified by Prep-HPLC using method E eluted with a gradient of 3060% ACN. This resulted in 82 mg (80.3%) of Example 1 as a white solid.

Example 1 MS-ESI: 418.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (s, 1H), 7.57 (s, 2H), 6.87 (s, 1H), 6.85 (s, 1H), 5.04 (s, 1H), 2.79 (t, J=7.4 Hz, 4H), 2.71-2.63 (m, 4H), 2.42 (s, 3H), 1.94 (tt, J=7.4 and 7.4 Hz, 4H), 1.40 (s, 6H). Step 3: Chiral Separation

The product obtained as described in the previous step (70 mg) was resolved by Chiral-Prep-HPLC using the following conditions: Column, ChiralPak ID, 2*25 cm, 5 um; mobile phase, Hex and EtOH (hold 20% EtOH over 18 min); Flow rate, 20 mL/min; Detector, UV 254/220 nm. This resulted in 26.8 mg of Example 2 (front peak, 99% ee) as a white solid and 27.7 mg (second peak, 99.3% ee) of Example 3 as a white solid.

Example 2 MS-ESI: 418.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (s, 1H), 7.57 (s, 2H), 6.87 (s, 1H), 6.85 (s, 1H), 5.03 (s, 1H), 2.78 (t, J=7.2 Hz, 4H), 2.73-2.60 (m, 4H), 2.41 (s, 3H), 1.93 (tt, J=7.2 and 7.2 Hz, 4H), 1.39 (s, 6H). Example 3 MS-ESI: 418.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (s, 1H), 7.58 (s, 2H), 6.87 (s, 1H), 6.85 (s, 1H), 5.03 (s, 1H), 2.78 (t, J=7.2 Hz, 4H), 2.73-2.60 (m, 4H), 2.41 (s, 3H), 1.93 (tt, J=7.2 and 7.2 Hz, 4H), 1.39 (s, 6H).

Single crystal X-ray crystallographic analysis was performed on compound 181a. FIG. 1 shows ball and stick models of the asymmetrical unit containing two crystallographically independent molecules of compound 181a, with hydrogen atoms omitted for clarity. Table M below shows fractional atomic coordinates of compound 181a.

TABLE M Fractional Atomic Coordinates (×10⁴) and Equivalent Isotropic Displacement Parameters (Å² × 10³) for Example 2. U_(eq) is defined as ⅓ of the trace of the orthogonalised U_(IJ) tensor. Atom x y z U(eq) S1 722.5(7)  5368.3(5)  6903.3(4)  14.52(18) S2 4304.8(7)  505.4(5)  3262.9(4)  16.15(18) O1 2143(2) 6680.8(16)  8220.2(13)  16.1(4) O2 −195(2) 4624.4(17)  6478.0(14)  21.9(5) O5 2874(2) 1624.4(17)  1805.2(15)  22.8(5) O6 5238(2) −141.6(18)  3795.4(15)  25.6(5) O3 1492(3) 5769.7(18)  5397.8(14)  25.5(5) O7 2974(2) 2151.0(17)  3638.1(14)  24.6(5) N1  51(2) 7218.5(19)  8513.8(16)  14.6(5) N2  59(3) 5986.0(18)  7536.5(16)  15.3(5) O4 2422(3) 8513(2) 4297.8(17)  34.3(6) N4 4956(2) 2247(2) 1576.1(16)  16.9(5) O8 2771(3) 3430(2) 6070.3(18)  36.7(6) N5 4980(3) 1071.7(19)  2602.6(17)  16.6(5) N3 2120(3) 4817(2) 7347.5(17)  16.3(5) C13  854(3) 6633(2) 8105.0(18)  12.9(6) C1  605(3) 7947(2) 9133.7(19)  14.4(6) N6 2978(3) −121(2) 2801.8(19)  20.2(6) C22 4388(3) 2952(2)  936.5(19) 16.2(6) C24 5733(3) 2203(2) −207(2) 18.3(6) C34 4164(3) 1656(2) 1979(2) 16.6(6) C11 −695(3) 7200(2) 10304.5(19)  17.2(6) C12  267(3) 7915(2) 9953.6(19)  14.2(6) C23 4754(3) 2918(2)  127(2) 17.0(6) C27 4221(3) 3614(2) −494(2) 18.1(6) C8  800(3) 8626(2) 10566(2)  17.0(6) C28 3315(3) 4357(2) −324(2) 18.6(6) C4 2436(4) 10034(2)  8218(2) 23.3(7) C7 1688(3) 9377(2) 10382(2)  16.9(6) C29 2969(3) 4399(2)  492(2) 18.0(6) C9  237(3) 8445(2) 11388(2)  20.4(6) C38 2557(3) 2633(3) 4320(2) 24.9(7) C2 1458(3) 8717(2) 8931.9(19)  15.1(6) C6 2005(3) 9409(2) 9557(2) 17.2(6) C26 4804(3) 3424(2) −1310(2)  21.8(7) C31 2476(4) 5023(2) 1822(2) 24.4(7) C5 2927(3) 10137(2)  9193(2) 19.6(6) C16 2044(3) 7389(3) 5427(2) 22.4(7) C25 5416(4) 2367(3) −1181(2)  24.1(7) C15 1514(3) 7144(2) 6188(2) 21.6(6) C33 3503(3) 3713(2) 1124(2) 16.9(6) C37 3005(3) 2117(3) 5067(2) 23.8(7) C30 2028(3) 5128(2)  844(2) 20.5(6) C10 −360(4) 7379(2) 11275(2)  23.9(7) C36 3748(3) 1285(3) 4821(2) 24.5(7) C17 2020(4) 6535(3) 4974(2) 28.3(7) C14 1181(3) 6178(2) 6137.8(19)  19.0(6) C35 3710(3) 1326(2) 3973(2) 23.7(7) C19 2583(3) 8401(3) 5214(2) 26.0(7) C3 1902(3) 8960(2) 8090(2) 19.0(6) C32 3002(3) 3944(2) 1954(2) 21.0(6) C40 2768(4) 2390(3) 5955(2) 33.7(8) C20 1804(4) 9231(3) 5566(3) 34.6(8) C39 1810(4) 3575(3) 4092(3) 35.7(8) C42 1313(4) 2062(3) 6087(3) 40.3(9) C21 4139(4) 8447(3) 5541(3) 40.0(9) C18 2406(5) 6256(3) 4130(3) 44.7(10) C41 3893(5) 1934(4) 6622(3) 54.3(12)

Single crystal X-ray crystallographic analysis was performed on compound 181b. FIG. 2 shows ball and stick models of the asymmetrical unit containing two crystallographically independent molecules of compound 181b, with hydrogen atoms omitted for clarity. Table N below shows fractional atomic coordinates of compound 181b.

TABLE N Fractional Atomic Coordinates (×10⁴) and Equivalent Isotropic Displacement Parameters (Å² × 10³) for Example 3. U_(eq) is defined as ⅓ of the trace of the orthogonalised U_(IJ) tensor. Atom x y z U(eq) S1 9264.0(7)  4621.3(5)  3094.0(4)  16.15(17) S2 5705.1(7)  9485.8(5)  6733.7(4)  19.00(17) O1 7853(2) 3305.2(16)  1778.9(13)  18.6(4) O7 7027(2) 7842.4(18)  6357.2(15)  26.4(5) O2 10182(2)  5364.5(17)  3520.0(14)  23.6(5) O5 7131(2) 8368.0(19)  8192.5(15)  25.5(5) O3 8512(3) 4220.7(18)  4605.0(14)  26.6(5) O6 4770(2) 10133.7(19)  6200.8(15)  28.4(5) O8 7211(3) 6563(2) 3921.7(19)  38.6(7) O4 7597(3) 1484(2) 5713.0(18)  37.3(6) N2 9933(3) 4006.4(19)  2465.8(16)  17.8(5) N1 9943(2) 2773(2) 1482.7(16)  16.3(5) N4 5051(3) 7745(2) 8421.8(17)  20.2(5) N3 7870(3) 5173(2) 2653.4(17)  18.4(5) N5 5031(3) 8923(2) 7390.2(17)  19.9(5) C14 9136(3) 3353(2) 1894.3(18)  15.8(6) C1 9391(3) 2043(2)  864.7(19) 17.4(6) N6 7031(3) 10109(2)  7191.6(19)  23.0(6) C30 5618(3) 7045(2) 9058(2) 19.3(6) C6 9205(3) 1370(2) −570(2) 20.1(6) C53 7446(4) 7363(3) 5675(2) 26.1(7) C32 4273(3) 7792(2) 10199(2)  20.6(6) C2 9731(3) 2078(2)  44.2(19) 16.8(6) C43 5846(3) 8333(2) 8016(2) 20.2(6) C3 10685(3)  2795(2) −304(2) 20.3(6) C37 7028(3) 5597(2) 9506(2) 21.2(6) C7 8316(3)  620(2) −386(2) 20.2(6) C35 5773(3) 6383(2) 10493(2)  20.7(6) C10 7573(4)  −36(3) 1780(2) 27.4(7) C36 6681(3) 5639(2) 10322(2)  21.2(6) C22 8481(3) 2845(3) 3816(2) 23.0(6) C8 8002(3)  584(2)  440(2) 20.3(6) C39 7525(4) 4977(3) 8177(2) 28.0(7) C31 5248(3) 7078(2) 9867(2) 19.6(6) C52 6981(3) 7875(3) 4927(2) 24.2(7) C12 8541(3) 1280(2) 1066.4(19)  18.0(6) C34 5191(4) 6574(3) 11302(2)  24.8(7) C51 6252(4) 8707(3) 5170(2) 26.7(7) C33 4585(4) 7630(3) 11175(2)  27.6(7) C24 7990(4) 3461(3) 5032(2) 30.5(8) C23 7962(3) 2603(3) 4580(2) 24.0(7) C50 6302(4) 8662(3) 6020(2) 25.4(7) C9 7077(3) −142(2)  804(2) 23.6(7) C38 7972(3) 4873(2) 9155(2) 23.5(7) C5 9763(4) 1551(3) −1391(2)  24.9(7) C41 6502(3) 6286(2) 8872(2) 20.5(6) C21 8811(3) 3816(2) 3866.6(19)  20.4(6) C4 10356(4)  2619(3) −1277(2)  28.3(7) C11 8099(3) 1036(2) 1909(2) 22.6(6) C40 7006(3) 6055(3) 8044(2) 24.5(6) C25 7419(4) 1599(3) 4793(2) 26.8(7) C58 8189(4) 6425(3) 5905(3) 37.6(9) C54 7221(4) 7601(3) 4036(2) 34.1(8) C27 8195(4)  774(3) 4438(3) 38.1(9) C29 7607(6) 3737(3) 5874(3) 46.7(10) C56 8674(4) 7924(3) 3907(3) 42.4(10) C28 5872(4) 1551(3) 4471(3) 44.2(10) C57 6101(6) 8060(4) 3369(3) 58.9(14)

Example 4

Example 4 (101′) N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Example 4 (above) was synthesized according to the general methods in Schemes 2 and 3, as illustrated in Route 1 and Route 2 below.

Examples 5 and 6

Examples 5 and 6 (Stereochemistry Not Assigned) Examples 5 (101) and 6 (102) (S)- and (R)-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Examples 5 and 6 (above) were synthesized according to general methods shown in Schemes 2 and 3, as illustrated in Route 1 and Route 2 below.

Example 7

Example 7 (194) Tert-butyl N-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidoylcarbamate

Example 7 was synthesized according to general method shown in Scheme 3, as illustrated in Route 2 below.

Route 1

Step 1: N-(tert-butyldimethylsilyl)-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 50-mL round-bottom flask was placed a solution of N′-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (336 mg, 1.0 mmol) in THF (10 mL). To this solution was added NaH (60% wt, 80 mg, 2.0 mmol) in portions at 0° C. The solution was stirred at 0° C. for 15 minutes, and this was followed by the addition of a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (209 mg, 1.1 mmol) in THF (5 mL) dropwise with stirring at RT. The resulting solution was stirred for 12 h at RT. The reaction was then quenched by the addition of 10 mL of NH₄Cl (sat.). The resulting solution was extracted with 3×10 mL of DCM and the combined organic layers were concentrated under vacuum. This resulted in 535 mg (crude) of the title compound as a brown oil. MS-ESI: 535.0 (M+1).

Step 2: N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 50-mL round-bottom flask was placed a solution of N-(tert-butyldimethylsilyl)-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (535 mg, crude, 1.0 mmol) in THF (10 mL). To this solution was added HF/Py (70% wt, 143 mg, 5.0 mmol) dropwise at 0° C. The solution was stirred at RT for 4 h. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the combined organic layers were concentrated under vacuum. The crude product was purified by Prep-HPLC using Method E with ACN/water (20% to 60% in 10 minutes). This resulted in 189 mg (45%, 2 steps) of Example 4 as a white solid.

Example 4 MS-ESI: 421.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (br s, 1H), 8.04 (s, 1H), 7.80 (br s, 2H), 6.86 (s, 1H) 6.28 (s, 1H), 2.88-2.71 (m, 4H), 2.71-2.56 (m, 4H), 2.02-1.80 (m, 4H), 1.49 (s, 6H). Step 2: Chiral Separation

The product obtained as described in the previous step (189 mg) was resolved by Chiral-Prep-HPLC using the following conditions: Column, CHIRAL Cellulose-SB, 2*25 cm, 5 um; mobile phase, Hex (0.1%DEA) and EtOH (hold 20% EtOH over 16 min); Flow rate, 20 mL/min; Detector, UV 254/220 nm. This resulted in 70 mg of Example 5 (front peak, 99% ee 101) as a white solid and 65 mg of Example 6 (second peak, 97.5% ee 102) as a white solid. Absolute stereochemistry of these two isomers has not been assigned.

Example 5 MS-ESI: 421.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (br s, 1H), 8.05 (s, 1H), 7.83 (br s, 2H), 6.87 (s, 1H) 6.29 (s, 1H), 2.82-2.71 (m, 4H), 2.71-2.56 (m, 4H), 2.02-1.80 (m, 4H), 1.50 (s, 6H). Example 6 MS-ESI: 421.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (br s, 1H), 8.05 (s, 1H), 7.83 (s, 2H), 6.87 (s, 1H) 6.27 (s, 1H), 2.82-2.71 (m, 4H), 2.71-2.56 (m, 4H), 2.02-1.80 (m, 4H), 1.50 (s, 6H).

Route 2:

Step 1: Tert-butyl N-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidoylcarbamate

Tert-butyl (amino(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ⁶-sulfaneylidene)carbamate (12 g, 37 mmol) was dissolved in dried THF (200 mL). To the solution was added NaH (17.7 g, 60%, 44 mmol) in portions at 0° C. under nitrogen atmosphere, and then the mixture was stirred at 0° C. for 0.5 h. Freshly prepared 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (7.4 g, 37 mmol) was dissolved in dried THF (50 mL) and the solution was added to the front mixture dropwise at 0° C. The mixture was stirred at RT for 1 h. The reaction was quenched with ice-water (100 mL), and the pH value of the resulting solution was adjusted to 6 with HCO₂H. The solution was extracted with EtOAc (3×200 mL) and the combined organic layers were dried over anhydrous Na₂SO₄ and concentrated to give 17.5 g of Example 7 as a crude grey solid.

Example 7 MS-ESI: 521.0 (M+1). ¹H NMR (300 MHz, MeOD-d₄) δ 8.14 (s, 1H), 6.89 (s, 1H), 3.00-2.60 (m, 8H), 2.20-1.90 (m, 4H), 1.51 (s, 6H), 1.37 (s, 9H). Step 2: N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

The crude tert-butyl (N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)-thiazole-5-sulfonimidoyl)carbamate (crude 17.5 g) was dissolved in THF (200 mL). To the solution was added HCl (200 mL, 4M in 1,4-dioxane) at RT. The mixture was stirred at RT overnight and concentrated. The residue was purified with SiO₂-gel column and eluted with MeOH/DCM (5%) and further purified by reverse column with MeOH/water (50% to 80% in 50 minutes) to give 12 g of Example 4 (51%, 2 steps) as a white solid.

Example 4 MS-ESI: 421.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (br s, 1H), 8.04 (s, 1H), 7.80 (br s, 2H), 6.86 (s, 1H) 6.28 (s, 1H), 2.88-2.71 (m, 4H), 2.71-2.56 (m, 4H), 2.02-1.80 (m, 4H), 1.49 (s, 6H). Step 3: Chiral Separation

The product obtained as described in the previous step (12 g) was resolved by Chiral-Prep-SFC using the following conditions: Column, CHIRALPAK IF, 2*25 cm, 5 um; Mobile Phase A: CO₂: 60, Mobile Phase B: MeOH (2 mM NH₃-MeOH): 40; Flow rate: 40 mL/min; Detector, UV 220 nm. This resulted in 3.8 g of Example 6 (front peak, 99% ee 102) as a white solid and 4.6 g of Example 5 (second peak, 97.5% ee 101) as a white solid. Absolute stereochemistry of these two isomers has not been assigned.

Example 5 MS-ESI: 421.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (br s, 1H), 8.05 (s, 1H), 7.83 (br s, 2H), 6.87 (s, 1H) 6.29 (s, 1H), 2.82-2.71 (m, 4H), 2.71-2.56 (m, 4H), 2.02-1.80 (m, 4H), 1.50 (s, 6H). Example 6 MS-ESI: 421.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (br s, 1H), 8.05 (s, 1H), 7.83 (s, 2H), 6.87 (s, 1H) 6.27 (s, 1H), 2.82-2.71 (m, 4H), 2.71-2.56 (m, 4H), 2.02-1.80 (m, 4H), 1.50 (s, 6H). Example 8

Example 8 (270) N′-(8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-hydroxypropan-2-yl)-N-methylthiophene-2-sulfonimidamide (Scheme 4)

Example 8 was synthesized according to the general method shown in Scheme 4.

Into a 50-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of 4-fluoro-8-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (110 mg, 0.51 mmol) in DCM (5 mL). To the solution were added TEA (153 mg, 1.51 mmol) and 4-(2-hydroxypropan-2-yl)-N′-methylthiophene-2-sulfonimidamide (120 mg, 0.51 mmol). The resulting solution was stirred for 14 h at RT and then was concentrated under vacuum. The crude product was purified by Prep-HPLC using method E eluted with a gradient of 30˜74% ACN. This resulted in 80 mg (35%) of Example 8 as a white solid.

Example 8 MS-ESI: 450.1 (M−1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (br s, 1H), 7.64 (s, 1H), 7.59-7.50 (m, 2H), 5.23 (s, 1H), 2.84-2.69 (m, 8H), 2.50 (s, 3H), 1.99 (t, J=7.2 Hz, 4H), 1.42 (d, J=2.8 Hz, 6H) Example 9 (204)

N′-((2,6-dimethylpyridin-4-yl)carbamoyl)-4-methyl-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide (Scheme 5)

Step 1: 4-Azido-2,6-dimethylpyridine

To the solution of 2,6-dimethylpyridine-4-carboxylic acid (151 mg, 1.0 mmol) in dried toluene (15 mL). To the solution was added DPPA (825 mg, 3.0 mmol) and TEA (303 mg, 3.0 mmol). The mixture was stirred at 60° C. for 4 h. The solution was concentrated under vacuum. This gave 900 mg (crude) of the title compound as yellow oil.

Step 2 & 3: N-(tert-butyldimethylsilyl)-N′-((2,6-dimethylpyridin-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-3-methylthiophene-2-sulfonimidamide

The 4-azido-2,6-dimethylpyridine (900 mg, crude) was dissolved in THF (20 mL). To the solution was added N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-3-methylthiophene-2-sulfonimidamide (349 mg, 1.0 mmol) and NaOH (120 mg, 3.0 mmol). The mixture was stirred at 50° C. for 12 h. The solution was diluted with water 20 mL, then the resulting solution was extracted with 3×20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous Na₂SO₄, then concentrated under vacuum. This gave 500 mg (crude) of the title compound as a yellow solid. MS-ESI: 497.0 (M+1).

Step 4: N′-((2,6-dimethylpyridin-4-yl)carbamoyl)-4-methyl-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide

Into a 50-mL round-bottom flask was placed a solution of N-(tert-butyldimethylsilyl)-N′-((2,6-dimethylpyridin-4-yl)carbamoyl)-4-methyl-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide (500 mg, crude) in THF (10 mL), to this solution was added HF/Py (70% wt, 143 mg, 5.0 mmol) dropwise at 0° C. The solution was stirred at RT for 4 h. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the combined organic layers were concentrated under vacuum. The crude product was purified by Prep-HPLC using method E eluted with a gradient of ACN/water (10% to 30% in 10 minutes). This resulted in 15 mg (4%, 4 steps) of Example 9 as a white solid. MS-ESI: 383.0 (M+1). ¹H NMR (300 MHz, DMSO-d₆) δ 9.31 (s, 1H), 7.53 (br s, 2H), 7.31 (s, 1H), 7.14 (s, 2H), 5.81 (s, 1H), 2.28 (s, 6H), 2.23 (s, 3H), 1.50 (s, 6H).

TABLE 16 Examples in the following table were prepared using similar conditions as described in Example 1 and Scheme 1 from appropriate starting materials. Final Target Exact Mass Example # Number Structure IUPAC Name [M + H]⁺ 10 180

N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-4-(2- hydroxypropan-2-yl)-5-methylfuran-2- sulfonimidamide 440.2 11 190

N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-4-(2- hydroxypropan-2- yl)benzenesulfonimidamide 436.2 12 182

N′-(1,2,3,5,6,7-hexahydro-s-indacen-4- ylcarbamoyl)-4-(2-hydroxypropan-2-yl)-5- methylthiophene-2-sulfonimidamide 434.1 13 191

2-fluoro-N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-4-(2- hydroxypropan-2- yl)benzenesulfonimidamide 432.2 14 177

N′-(8-chloro-1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-4-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide 452.0(M − 1) 15 185

N′-(4-cyano-3-fluoro-2,6- diisopropylphenylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamide 468.2 16 186

N′-(1,2,3,5,6,7-hexahydro-s-indacen-4- ylcarbamoyl)-1-isopropyl-1H-pyrazole-3- sulfonimidamide 388.1 17 187

N′-(4-(difluoromethoxy)-2,6- diisopropylphenylcarbamoyl)-3-fluoro-5-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide 508.2 18 188

N′-(4-(difluoromethoxy)-2-ethyl-6- isopropylphenylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamide 477.1 19 192

N′-(1,2,3,5,6,7-hexahydro-s-indacen-4- ylcarbamoyl)-4-(2-hydroxypropan-2-yl)-2- methylbenzenesulfonimidamide 426.2(M − 1) 20 189

N′-(2-cyclopropyl-4-(difluoromethoxy)-6- isopropylphenylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamide 487.1(M − 1) 21 178

N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamide 441.1(M − 1) 22 193

N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-3-(2- hydroxypropan-2- yl)benzenesulfonimidamide 436.1 23 170

N′-(4-cyano-6-cyclopropyl-3-fluoro-2- isopropylphenylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamide 466.1 24 168

N′-(4-(difluoromethoxy)-2,6- diisopropylphenylcarbamoyl)-5-(2- hydroxypropan-2-yl)-3-methylthiophene-2- sulfonimidamide 504.3 25 171

N′-(4-(difluoromethoxy)-2,6- diisopropylphenylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamide 491.1 26 122

N′-(8-cyano-1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-4-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide 443.1 (M − 1) 27 120

N′-(8-(difluoromethoxy)-1,2,3,5,6,7- hexahydro-s-indacen-4-ylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamide 487.1 28 125

4-((dimethylamino)methyl)-N′-(1,2,3,5,6,7- hexahydro-s-indacen-4- ylcarbamoyl)benzenesulfonimidamide 413.3 29 129

N′-(2-cyclopropyl-4-(difluoromethoxy)-6- isopropylphenylcarbamoyl)-4-(2- hydroxypropan-2-yl)-2- methylbenzenesulfonimidamide 496.2 30 213

3-fluoro-N′-(8-fluoro-1,2,3,5,6,7-hexahydro- s-indacen-4-ylcarbamoyl)-5-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide 456.1 31 207

4-(2-hydroxypropan-2-yl)-5-methyl-N′-((3- methyl-1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)furan-2-sulfonimidamide 432.2 32 195

4-(2-hydroxypropan-2-yl)-5-methyl-N′-((1- methyl-1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)furan-2-sulfonimidamide 432.2

TABLE 17 Examples in the following table were prepared using similar conditions as described in Example 4-route 1 and Scheme 2 from appropriate starting materials. Example Final Target Exact Mass # Number Structure IUPAC Name [M + H]⁺ 33 179

N′-(4-cyano-3-fluoro-2,6- diisopropylphenylcarbamoyl)-4-(2- hydroxypropan-2-yl)-5-methylfuran-2- sulfonimidamide 465.2 34 105

N′-(8-fluoro-1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-3-(2- hydroxypropan-2- yl)benzenesulfonimidamide 432.2 35 121

N′-(4-cyano-2,6- diisopropylphenylcarbamoyl)-5-(2- hydroxypropan-2-yl)thiazole-2- sulfonimidamide 448.1 (M − 1) 36 145

4-((dimethylamino)methyl)-N′-(4- fluoro-2,6- diisopropylphenylcarbamoyl)benzene- sulfonimidamide 435.2 37 131

N′-(2-cyclopropyl-4-(difluoromethoxy)- 6-isopropylphenylcarbamoyl)-4- ((dimethylamino)methyl)benzene- sulfonimidamide 481.3 38 132

N′-(4-(difluoromethoxy)-2,6- diisopropylphenylcarbamoyl)-5-(2- hydroxypropan-2-yl)thiazole-2- sulfonimidamide 489.1 (M − 1) 39 144

N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-5-(2- hydroxypropan-2-yl)thiazole-2- sulfonimidamide 441.1 (M − 1) 40 149

N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-4-(2- hydroxypropan-2-yl)thiopene-2- sulfonimidamide 440.1 (M − 1) 41 152

N′-(8-chloro-1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-2-fluoro-4-(2- hydroxypropan-2- yl)benzenesulfonimidamide 466.2 42 150

N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-4- (methylsulfonyl)benzenesulfonimidamide 454.1 (M − 1) 43 167

N′-(8-cyano-1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamide 444.2 (M − 1) 44 106

N′-(8-fluoro-1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamide 437.1 (M − 1) 45 107

N′-(8-fluoro-1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-4-(2- hydroxypropan-2-yl)-5-methylfuran-2- sulfonimidamide 436.2 46 110

N′-(1,2,3,5,6,7-hexahydro-s-indacen-4- ylcarbamoyl)-3-(2-hydroxypropan-2- yl)benzenesulfonimidamide 414.2 47 151

2-fluoro-N′-(8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-ylcarbamoyl)-4- (2-hydroxypropan-2- yl)benzenesulfonimidamide 448.1 (M − 1) 48 154

4-((dimethylamino)methyl)-2-fluoro-N′- (1,2,3,5,6,7-hexahydro-s-indacen-4- ylcarbamoyl)benzenesulfonimidamide 431.2 49 148

N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)-5-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide 442.2 50 153

2-chloro-N′-(8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-ylcarbamoyl)-4- (2-hydroxypropan-2- yl)benzenesulfonimidamide 464.1 (M − 1) 51 109

3-((dimethylamino)methyl)-N′- (1,2,3,5,6,7-hexahydro-s-indacen-4- ylcarbamoyl)benzenesulfonimidamide 411.1 (M − 1) 52 135

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-4-(2-hydroxypropan-2- yl)-3-methylbenzenesulfonimidamide 428.2 53 134

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-2-(2-hydroxypropan-2- yl)-4-methylthiazole-5-sulfonimidamide 435.1 54 130

N′-((2-cyclopropyl-4-(difluoromethoxy)- 6-isopropylphenyl)carbamoyl)-2-fluoro- 4-(2-hydroxypropan-2- yl)benzenesulfonimidamide 500.2 55 212

2-fluoro-N′-((8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-5- (2-hydroxypropan-2- yl)benzenesulfonimidamide 450.2 56 205

3-fluoro-N′-((8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-5- (2-hydroxypropan-2- yl)benzenesulfonimidamide 450.2 57 143

N′-((4-(difluoromethoxy)-2,6- diisopropylphenyl)carbamoyl)-5-(2- hydroxypropan-2-yl)-4- methylthiophene-2-sulfonimidamide 504.2 58 206

4-fluoro-N′-((8-fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-3- (2-hydroxypropan-2- yl)benzenesulfonimidamide 450.2 59 108

N′-((8-fluoro-1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)-4-methylthiazole- 5-sulfonimidamide 453.1 60 202

3-fluoro-N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-4-(2- hydroxypropan-2- yl)benzenesulfonimidamide 432.2 61 208

N′-((8-fluoro-1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)thiazole-2- sulfonimidamide 439.1 62 197

N′-((3-fluoro-2,6- diisopropylphenyl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamide 443.2 63 196

N′-((4-fluoro-2,6- diisopropylphenyl)carbamoyl)-3- (methylsulfonyl)benzenesulfonimidamide 456.1 64 124

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-5-(2-hydroxypropan-2- yl)thiazole-2-sulfonimidamide 421.1 65 173

N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-3-fluoro- 5-(2-hydroxypropan-2-yl)thiophene-2- sulfonimidamide 467.2 66 172

N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-3,5-bis(2- hydroxypropan-2- yl)benzenesulfonimidamide 501.2 67 174

3-cyano-N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl-5-(2- hydroxypropan-2- yl)benzenesulfonimidamide 468.2 68 158

N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-3- (hydroxymethyl)-4-(2-hydroxypropan-2- yl)benzenesulfonimidamide 473.2 69 220

N′-((8-cyano-1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-4- (hydroxymethyl)-2-(2-hydroxypropan-2- yl)thiazole-5-sulfonimidamide 476.1 70 157

N-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-4- (hydroxymethyl)-2-(2-hydroxypropan-2- yl)thiazole-5-sulfonimidamide 480.2 71 161

N-((4-cyano-3-fluoro-2,6- diisopropylphenyl)carbamoyl)-4- (hydroxymethyl)-2-(2-hydroxypropan-2- yl)thiazole-5-sulfonimidamide 498.2 72 159

N′-((4-cyano-3-fluoro-2,6- diisopropylphenyl)carbamoyl)-2-(1,2- dihydroxypropan-2-yl)thiazole-5- sulfonimidamide 484.1 73 165

N′-((4-cyano-2,6- diisopropylphenyl)carbamoyl)-4- (methylsulfonyl)benzenesulfonimidamide 463.1 74 183

N′-(1,2,3,5,6,7-hexahydro-s-indacen-4- ylcarbamoyl)-4-(2-hydroxypropan-2- yl)thiophene-2-sulfonimidamide 418.1 (M − 1) 75 176

N′-(8-fluoro-1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-4-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide 438.0 76 136

N′-(1,2,3,5,6,7-hexahydro-s-indacen-4- ylcarbamoyl)-4-(2-hydroxypropan-2- yl)furan-2-sulfonimidamide 404.2 77 209

N′-(1,2,3,5,6,7-hexahydro-s-indacen-4- ylcarbamoyl)-4-(2-hydroxypropan-2- yl)thiazole-2-sulfonimidamide 421.1

TABLE 18 Examples in the following table were prepared using similar conditions as described in Example 9 and Scheme 5 from appropriate materials. Final Target Exact Mass Example # Number Structure IUPAC Name [M + H]⁺ 78 203

N-((2,6-dimethylpyridin-4- yl)carbamoyl)-5-(2- hydroxypropan-2-yl)thiophene- 2-sulfonimidamide 369.1

TABLE 19 Examples in the following table were obtained from chiral HPLC resolutions of racemic examples described above. The chiral column and eluents are listed in the table. Final LC- Target MS Ex. Num- [M + # ber Structure IUPAC Name Column Eluents H]⁺ 79 180a or 180b

(S)-or (R)- N′-(4-fluoro-2,6- diisopropylphenyl- carbamoyl)- 4-(2- hydroxypropan-2-yl)- 5-methylfuran-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 20% EtOH in Hex 440.3 80 180b or 180a

(R)-or (S)- N′-(4-fluoro-2,6- diisopropylphenyl- carbamoyl)- 4-(2- hydroxypropan-2-yl)- 5-methylfuran-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 20% EtOH in Hex 440.3 81 179a or 179b

(S)-or (R)- N′-(4-cyano- 3-fluoro-2,6- diisopropylphenyl- carbamoyl)- 4-(2- hydroxypropan-2-yl)- 5-methylfuran-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 23% EtOH in Hex 465.3 82 179b or 179a

(R)-or (S)- N′-(4-cyano- 3-fluoro-2,6- diisopRopylphenyl- carbamoyl)- 4-(2- hydroxypropan-2-yl)- 5-methylfuran-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 23% EtOH in Hex 465.3 83 190a or 190b

(S)-or (R)- N′-(4-fluoro-2,6- diisopropylphenyl- carbamoyl)- 4-(2- hydroxypropan-2- yl) benzenesulfonimidamide ChiralPak ID, 2*25 cm, 5 um 20% EtOH in Hex 436.2 84 190b or 190a

(R)-or (S)- N′-(4-fluoro-2,6- diisopropylphenyl- carbamoyl)- 4-(2- hydroxypropan-2- yl) benzenesulfonimidamide ChiralPak ID, 2*25 cm, 5 um 20% EtOH in Hex 436.2 85 182a or 182b

(S)-or (R)- N′-(1,2,3,5,6,7-hexahydro- s-indacen-4- ylcarbamoyl)-4-(2- hydroxypropan-2-yl)-5- methylthiophene-2- sulfonimidamide ChiralPak IC, 2*25 cm, 5 um 20% EtOH in Hex 434.1 86 182b or 182a

(R)-or (S)- N′-(1,2,3,5,6,7-hexahydro- s-indacen-4- ylcarbamoyl)-4-(2- hydroxypropan-2-yl)-5- methylthiophene-2- sulfonimidamide ChiralPak IC, 2*25 cm, 5 um 20% EtOH in Hex 434.1 87 191a or 191b

(S)-or (R)- 2-fluoro-N′-(1,2,3,5,6,7- hexahydro-s- indacen-4- ylcarbamoyl)-4-(2- hydroxypropan-2- yl) benzenesulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% IPA in Hex (0.1% DEA) 430.1 (M − 1) 88 191b or 191a

(R)-or (S)- 2-fluoro-N′-(1,2,3,5,6,7- hexahydro-s- indacen-4-ylcarbamoyl)-4-(2- hydroxypropan-2- yl)benzenesulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% IPA in Hex (0.1% DEA) 430.1 (M − 1) 89 177a or 177b

(S)-or (R)- N′-(8-chloro-1,2,3,5,6,7- hexahydro-s- indacen-4- ylcarbamoyl)-4-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 20% EtOH in Hex (0.1% DEA) 452.0 (M − 1) 90 177b or 177a

(R)-or (S)- N′-(8-chloro-1,2,3,5,6,7- hexahydro-s- indacen-4- ylcarbamoyl)-4-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 20% EtOH in Hex (0.1% DEA) 452.0 (M − 1) 91 185a or 185b

(S)-or (R)- N′-(4-cyano-3- fluoro-2,6- diisopropylphenyl- carbamoyl)- 2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% EtOH in Hex (0.1% DEA) 466.1 (M − 1) 92 185b or 185a

(R)-or (S)- N′-(4-cyano-3- fluoro-2,6- diisopropylphenyl- carbamoyl)- 2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% EtOH in Hex (0.1% DEA) 466.1 (M − 1) 93 186a or 186b

(S)-or (R)- N′-(1,2,3,5,6,7- hexahydro- s-indacen-4- ylcarbamoyl)-1- isopropyl- 1H-pyrazole-3 sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% EtOH in Hex (0.1% DEA) 388.1 94 186b or 186a

(R)-or (S)- N′-(1,2,3,5,6,7- hexahydro- s-indacen-4- ylcarbamoyl)-1- isopropyl- 1H-pyrazole-3- sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% EtOH in Hex (0.1% DEA) 388.1 95 187a or 187b

(S)-or (R)- N′-(4- (difluoromethoxy)-2,6- diisopropylphenyl- carbamoyl)- 3-fluoro-5-(2- hydroxypropan-2-yl) thiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 20% EtOH in Hex (0.1% DEA) 508.2 96 187b or 187a

(R)-or (S)- N′-(4- (difluoromethoxy)-2,6- diisopropylphenyl- carbamoyl)- 3-fluoro-5- (2-hydroxypropan-2-yl) thiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 20% EtOH in Hex (0.1% DEA) 508.2 97 188a or 188b

(S)-or (R)- N′-(4-(difIuoromethoxy)- 2-ethyl-6- isopropylphenyl- carbamoyl)- 2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% IPA in Hex (0.1% DEA) 477.2 98 188b or 188a

(R)-or (S)- N′-(4-(difluoromethoxy)- 2-ethyl-6- isopropylphenyl- carbamoyl)- 2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% IPA in Hex (0.1% DEA) 477.2 99 192a or 192b

(S)-or (R)- N′-(1,2,3,5,6,7-hexahydro- s-indacen-4- ylcarbamoyl)-4-(2- hydroxypropan-2-yl)-2- methylbenzene- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% EtOH in Hex (0.1% DEA) 428.2 100 192b or 192a

(R)-or (S)- N′-(1,2,3,5,6,7-hexahydro- s-indacen-4- ylcarbamoyl)-4-(2- hydroxypropan-2-yl)-2- methylbenzene- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% EtOH in Hex (0.1% DEA) 428.2 101 189a or 189b

(S)-or (R)- N′-(2-cyclopropyl-4- (difluoromethoxy)-6- isopropylphenyl- carbamoyl)- 2-(2- hydroxypropan-2-yl) thiazole-5- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 50% IPA in Hex (0.1% DEA) 489.3 102 189b or 189a

(R)-or (S)- N′-(2-cyclopropyl-4- (difluoromethoxy)-6- isopropylphenyl- carbamoyl)- 2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 50% IPA in Hex (0.1% DEA) 489.2 103 178a or 178b

(S)-or (R)- N′-(4-fluoro-2,6- diisopropylphenyl- carbamoyl)- 2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% IPA (0.1% DEA) in Hex: DCM = 3:1 443.2 104 178b or 178a

(R)-or (S)- N′-(4-fluoro-2,6- diisopropylphenyl- carbamoyl)- 2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% IPA (0.1% DEA) in Hex: DCM = 3:1 443.1 105 193a or 193b

(S)-or (R)- N′-(4-fluoro-2,6- diisopropylphenyl- carbamoyl)- 3-(2- hydroxypropan-2- yl) benzenesulfonimidamide ChiralPak IG, 2*25 cm, 5 um 20% IPA in Hex (0.1% DEA) 436.2 106 193b or 193a

(R)-or (S)- N′-(4-fluoro-2,6- diisopropylphenyl- carbamoyl)- 3-(2- hydroxypropan-2- yl) benzenesulfonimidamide ChiralPak IG, 2*25 cm, 5 um 20% IPA in Hex (0.1% DEA) 436.2 107 170a or 170b

(S)-or (R)- N′-(4-cyano-6- cyclopropyl-3-fluoro-2- isopropylphenyl- carbamoyl)- 2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidaimide ChiralPak IG, 2*25 cm, 5 um 15% EtOH in Hex (0.1% DEA) 466.1 108 170b or 170a

(R)-or (S)- N′-(4-cyano-6- cyclopropyl-3-fluoro-2- isopropylphenyl- carbamoyl)- 2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 15% EtOH in Hex (0.1% DEA) 466.1 109 168a or 168b

(S)-or (R)- N′-(4- (difluoromethoxy)-2,6- diisopropylphenyl- carbamoyl)- 5-(2- hydroxypropan-2-yl)-3- methylthiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% IPA in Hex (0.1% DEA) 504.2 110 168b or 168a

(R)-or (S)- N′-(4- (difluoromethoxy)-2,6- diisopropylphenyl- carbamoyl)- 5-(2- hydroxypropan-2-yl)-3- methylthiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% IPA in Hex (0.1% DEA) 504.2 111 171a or 171b

(S)-or (R)- N′-(4- (difluoromethoxy)-2,6- diisopropylphenyl- carbamoyl)- 2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 50% IPA in Hex: DCM = 1:1 489.1 (M − 1) 112 171b or 171a

(R)-or (S)- N′-(4- (difluoromethoxy)-2,6- diisopropylphenyl- carbamoyl)- 2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 50% IPA in Hex: DCM = 1:1 489.1 (M − 1) 113 122a or 122b

(S)-or (R)- N′-(8-cyano-1,2,3,5,6,7- hexahydro-s- indacen-4- ylcarbamoyl)-4-(2- hydroxypropan-2-yl) thiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% IPA in Hex 443.1 (M − 1) 114 122b or 122a

(R)-or (S)- N′-(8-cyano-1,2,3,5,6,7- hexahydro-5- indacen-4- ylcarbamoyl)-4-(2- hydroxypropan-2-yl) thiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% IPA in Hex 443.1 (M − 1) 115 120a or 120b

(S)-or (R)- N′-(8-(difluoromethoxy)- 1,2,3,5,6,7- hexahydro-s-indacen-4- ylcarbamoyl)-2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide Chiral ART Cellulose- SB, 2*25 cm, 5 um 20% EtOH in Hex (0.1% DEA) 485.1 (M − 1) 116 120b or 120a

(R)-or (S)- N′-(8-(difluoromethoxy)- 1,2,3,5,6,7- hexahydro-5-indacen-4- ylcarbamoyl)-2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide Chiral ART Cellulose- SB, 2*25 cm, 5 um 20% EtOH in Hex (0.1% DEA) 485.1 (M − 1) 117 125a or 125b

(S)-or (R)- 4-((dimethylamino) methyl)- N′-(1,2,3,5,6,7- hexahydro-s-indacen-4- ylcarbamoyl) benzenesulfonimidamide ChiralPak ID, 2*25 cm, 5 um 50% IPA in Hex: DCM = 3:1 413.2 118 125b or 125a

(R)-or (S)- 4-((dimethylamino) methyl)- N′-(1,2,3,5,6,7- hexahydro-s- indacen-4- ylcarbamoyl) benzenesulfonimidamide ChiralPak ID, 2*25 cm, 5 um 50% IPA in Hex: DCM = 3:1 413.2 119 129a or 129b

(S)-or (R)- N′-(2-cyclopropyl-4- (difluoromethoxy)-6- isopropylphenyl- carbamoyl)- 4-(2- hydroxypropan-2-yl)-2- methylbenzene- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 50% IPA in Hex: DCM = 3:1 496.2 120 129b or 129a

(R)-or (S)- N′-(2-cyclopropyl-4- (difluoromethoxy)-6- isopropylphenyl- carbamoyl)- 4-(2- hydroxypropan-2-yl)-2- methylbenzene- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 50% IPA in Hex: DCM = 3:1 496.2 121 112a or 112b

(S)-or (R)- 3-fluoro-N′-(8-fluoro- 1,2,3,5,6,7-hexahydro- s-indacen-4- ylcarbamoyl)-5-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 15% EtOH in Hex (0.1% DEA) 456.1 122 112b or 112a

(R)-or (S)- 3-fluoro-N′-(8-fluoro- 1,2,3,5,6,7-hexahydro- 5-indacen-4- ylcarbamoyl)-5-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 15% EtOH in Hex (0.1% DEA) 456.1 128 105a or 105b

(S)-or (R)- N′-fluoro-1,2,3,5,6,7- hexahydro-s- indacen-4- ylcarbamoyl)-3-(2- hydroxypropan-2- yl) benzenesulfonimidamide ChiralPak ID, 2*25 cm, 5 um 40% EtOH in Hex 432.1 129 105b or 105a

(R)-or (S)- N′-(8-fluoro-1,2,3,5,6,7- hexahydro-s- indacen-4-ylcarbamoyl)-3-(2- hydroxypropan-2- yl)benzenesulfommidamide ChiralPak ID, 2*25 cm, 5 um 40% EtOH in Hex 432.1 130 121a or 121b

(S)-or (R)- N′-(4-cyano-2,6- diisopropylphenyl- carbamoyl)- 5-(2- hydroxypropan-2- yl)thiazole-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 40% EtOH in Hex 448.1 (M − 1) 131 121b or 121a

(R)-or (S)- N′-(4-cyano-2,6- diisopropylphenyl- carbamoyl)- 5-(2- hydroxypropan-2- yl)thiazole-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 40% EtOH in Hex 448.1 (M − 1) 132 145a or 145b

(S)-or (R)- 4-((dimethylamino) methyl)-N′-(4-fluoro- 2,6- diisopropylphenyl- carbamoyl) benzenesulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% EtOH in Hex 435.2 133 145b or 145a

(R)-or (S)- 4-((dimethylamino) methyl)-N′-(4-fluoro- 2,6- diisopropylphenyl- carbamoyl) benzenesulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% EtOH in Hex 435.2 134 131a or 131b

(S)-or (R)- N′-(2-cyclopropyl-4- (difluoromethoxy)-6- isopropylphenyl- carbamoyl)-4- ((dimethylamino)methyl) benzenesulfonimidamide ChiralPak IG, 2*25 cm, 5 um 50% EtOH in Hex 481.2 135 131b or 131a

(R)-or (S)- N′-(2-cyclopropyl-4- (difluoromethoxy)-6- isopropylphenyl- carbamoyl)-4- ((dimethylamino)methyl) benzenesulfonimidamide ChiralPak IG, 2*25 cm, 5 um 50% EtOH in Hex 481.2 136 225a or 225b

(S)-or (R)- N′-(4- (difluoromethoxy)-2,6- diisopropylphenyl- carbamoyl)- 5-(2- hydroxypropan-2- yl)thiazole-2- sulfonimidamide ChiralPak IF, 2*25 cm, 5 um 20% MeOH (0.1% TFA) in CO₂ 489.1 (M − 1) 137 225b or 225a

(R)-or (S)- N′-(4- (difluoromethoxy)-2,6- diisopropylphenyl- carbamoyl)- 5-(2- hydroxypropan-2- yl)thiazole-2- sulfonimidamide ChiralPak IF, 2*25 cm, 5 um 20% MeOH (0.1% TFA) in CO₂ 489.1 (M − 1) 138 144a or 144b

(S)-or (R)- N′-(4-fluoro-2,6- diisopropylphenyl- carbamoyl)- 5-(2- hydroxypropan-2- yl)thiazole-2- sulfonimidamide ChiralPak IF, 2*25 cm, 5 um 20% MeOH (0.1% TFA) in CO₂ 443.2 139 144b or 144a

(R)-or (S)- N′-(4-fluoro-2,6- diisopropylphenyl- carbamoyl)- 5-(2- hydroxypropan-2- yl)thiazole-2- sulfonimidamide ChiralPak IF, 2*25 cm, 5 um 20% MeOH (0.1% TFA) in CO₂ 443.1 140 149a or 149b

(S)-or (R)- N′-(4-fluoro-2,6- diisopropylphenyl- carbamoyl)-4-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% EtOH in Hex 440.1 (M − 1) 141 149b or 149a

(R)-or (S)- N′-(4-fluoro-2,6- diisopropylphenyl- carbamoyl)- 4-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% EtOH in Hex 440.1 (M − 1) 142 152a or 152b

(S)-or (R)- N′-(4-fluoro-2,6- diisopropylphenyl- carbamoyl)- 4-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% IPA in Hex 466.2 143 152b or 152a

(R)-or (S)- N′-(4-fluoro-2,6- diisopropylphenyl- carbamoyl)- 4-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% IPA in Hex 466.2 144 151a′ or 151b′

(S)-or (R)- N′-(4-fluoro-2,6- diisopropylphenylcarbamoyl)- 4- (methylsulfonyl) benzenesulfonimidamide Lux 5u Cellulose- 4, AXIA Packed, 2.12*25 cm, 5 um 35% MeOH (2 mM NH₃) in CO₂ 454.1 (M − 1) 145 151b′ or 151a′

(R)-or (S)- N′-(4-fluoro-2,6- diisopropylphenyl- carbamoyl)- 4- (methylsulfonyl) benzenesulfonimidamide Lux 5u Cellulose- 4, AXIA Packed, 2.12*25 cm, 5 um 35% MeOH (2 mM NH₃) in CO₂ 454.1 (M − 1) 146 167a or 167b

(S)-or (R)- N′-(8-cyano-1,2,3,5,6,7- hexahydro-s- indacen-4- ylcarbamoyl)-2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide ChiralPak IC, 2*25 cm, 5 um 30% EtOH in Hex (0.1% DEA) 444.1 (M − 1) 147 167b or 167a

(R)-or (S)- N′-(8-cyano-1,2,3,5,6,7- hexahydro-s- indacen-4- ylcarbamoyl)-2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide ChiralPak IC, 2*25 cm, 5 um 30% EtOH in Hex (0.1% DEA) 444.1 (M − 1) 148 107a or 107b

(S)-or (R)- N′-(8-fluoro-1,2,3,5,6,7- hexahydro-s- indacen-4- ylcarbamoyl)-4-(2- hydroxypropan-2-yl)- 5-methylfuran-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 50% IPA in Hex 434.1 (M − 1) 149 107b or 107a

(R)-or (S)- N′-(8-fluoro-1,2,3,5,6,7- hexahydro-s- indacen-4- ylcarbamoyl)-4-(2- hydroxypropan-2-yl)- 5-methylfuran-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 50% IPA in Hex 434.1 (M − 1) 150 110a or 110b

(S)-or (R)- N′-(1,2,3,5,6,7-hexahydro- s-indacen-4- ylcarbamoyl)-3-(2- hydroxypropan-2- yl)benzenesulfonimidamide ChiralPak IF, 2*25 cm, 5 um 30% EtOH in Hex 412.1 (M − 1) 151 110b or 110a

(R)-or (S)- N′-(1,2,3,5,6,7-hexahydro- s-indacen-4- ylcarbamoyl)-3-(2- hydroxypropan-2- yl)benzenesulfonimidamide ChiralPak IF, 2*25 cm, 5 um 30% EtOH in Hex 412.1 (M − 1) 152 151a or 151b

(S)-or (R)- 2-fluoro-N′-(8-fluoro- 1,2,3,5,6,7-hexahydro- s-indacen-4- ylcarbamoyl)-4-(2- hydroxypropan-2- yl)benzenesulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% IPA in Hex 448.1 (M − 1) 153 151b or 151a

(R)-or (S)- 2-fluoro-N′-(8-fluoro- 1,2,3,5,6,7-hexahydro- s-indacen-4- ylcarbamoyl)-4-(2- hydroxypropan-2- yl)benzenesulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% IPA in Hex 448.1 (M − 1) 154 154a or 154b

(S)-or (R)- 4-((dimethylamino) methyl)-2-fluoro-N′- (1,2,3,5,6,7-hexahydro- s-indacen-4- ylcarbamoyl) benzenesulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% EtOH in Hex 431.2 155 154b or 154a

(R)-or (S)- 4-((dimethylamino) methyl)-2-fluoro-N′- (1,2,3,5,6,7-hexahydro- s-indacen-4- ylcarbamoyl) benzenesulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% EtOH in Hex 431.2 156 148a or 148b

(S)-or (R)- N′-(4-fluoro-2,6- diisopropylphenyl- carbamoyl)- 5-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% EtOH in Hex 442.1 157 148b or 148a

(R)-or (S)- N′-(4-fluoro-2,6- diisopropylphenyl- carbamoyl)- 5-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% EtOH in Hex 442.1 158 153a or 153b

(S)-or (R)- 2-chloro-N′-(8- fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4- ylcarbamoyl)-4-(2- hydroxypropan-2- yl)benzenesulfonimidamide ChiralPak IF, 2*25 cm, 5 um 30% EtOH in Hex 464.1 (M − 1) 159 153a or 153b

(R)-or (S)- 2-chloro-N′-(8- fluoro-1,2,3,5,6,7- hexahydro-s-indacen- 4-ylcarbamoyl)-4-(2- hydroxypropan-2- yl)benzenesulfonimidamide ChiralPak IF, 2*25 cm, 5 um 30% EtOH in Hex 464.1 (M − 1) 160 109a or 109b

(S)-or (R)- 3-((dimethylamino) methyl)-N′-(1,2,3,5,6,7- hexahydro-s-indacen-4- ylcarbamoyl) benzenesulfonimidamide ChiralPak ID, 2*25 cm, 5 um 50% EtOH in Hex (0.1% DEA) 413.1 161 109b or 109a

(R)-or (S)- 3-((dimethylamino) methyl)-N′-(1,2,3,5,6,7- hexahydro-s-indacen-4- ylcarbamoyl) benzenesulfonimidamide ChiralPak ID, 2*25 cm, 5 um 50% EtOH in Hex (0.1% DEA) 413.1 162 135a or 135b

(S)-or (R)- N′-((1,2,3,5,6,7-hexahydro- s-indacen-4- yl)carbamoyl)-4-(2- hydroxypropan-2-yl)-3- methylbenzene- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% IPA in Hex 428.2 163 135b or 135a

(R)-or (S)- N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-4-(2- hydroxypropan-2-yl)-3- methylbenzene- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% IPA in Hex 428.2 164 134a or 134b

(S)-or (R)- N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)-4- methylthiazole-5- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% IPA in Hex 435.1 165 134b or 134a

(R)-or (S)- N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)-4- methylthiazole-5- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% IPA in Hex 435.1 166 130a or 130b

(S)-or (R)- N′-((2-cyclopropyl-4- (difluoromethoxy)-6- isopropylphenyl) carbamoyl)- 2-fluoro-4-(2- hydroxypropan-2- yl) benzenesulfonimidamide ChiralPak ID, 2*25 cm, 5 um 40% IPA in Hex 500.2 167 130b or 130a

(R)-or (S)- N′-((2-cyclopropyl-4- (difluoromethoxy)-6- isopropylphenyl) carbamoyl)- 2-fluoro-4-(2- hydroxypropan-2- yl) benzenesulfonimidamide ChiralPak ID, 2*25 cm, 5 um 40% IPA in Hex 500.2 168 212a or 212b

(S)-or (R)- 2-fluoro-N′-((8- fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-5-(2- hydroxypropan-2- yl) benzenesulfonimidamide ChiralPak ID, 2*25 cm, 5 um 40% EtOH in Hex 450.2 169 212b or 212a

(S)-or (R)- 2-fluoro-N′-((8- fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfonimidamide ChiralPak ID, 2*25 cm, 5 um 40% EtOH in Hex 450.2 170 205a or 205b

(R)-or (S)- 3-fluoro-N′-((8- fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfonimidamide Chiral ART Cellulose- SB, 2*25 cm, 5 um 30% EtOH in Hex 450.2 171 205a or 205b

(S)-or (R)- 3-fluoro-N′-((8- fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfonimidamide Chiral ART Cellulose- SB, 2*25 cm, 5 um 40% EtOH in Hex 450.2 172 143a or 143b

(S)-or (R)- N′-((4- (difluoromethoxy)-2,6- diisopropylphenyl) carbamoyl)-5-(2- hydroxypropan-2-yl)-4- methylthiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% EtOH in Hex 504.2 173 143b or 143a

(R)-or (S)- N′-((4- (difluoromethoxy)-2,6- diisopropylphenyl) carbamoyl)-5-(2- hydroxypropan-2-yl)-4- methylthiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% EtOH in Hex 504.2 174 206a or 206b

(S)-or (R)- 4-fluoro-N′-((8- fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-3-(2- hydroxypropan-2- yl) benzenesulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% EtOH in Hex (8 mM NH₃• MeOH) 450.2 175 206b or 206a

(R)-or (S)- 4-fluoro-N′-((8- fluoro-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-3-(2- hydroxypropan-2- yl) benzenesulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% EtOH in Hex (8 mM NH₃• MeOH) 450.2 176 108a or 108b

(S)-or (R)- N′-((8-fluoro-1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-2-(2- hydroxypropan-2-yl)- 4-methylthiazole-5- sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% IPA in Hex 453.1 177 108b or 108b

(R)-or (S)- N′-((8-fluoro-1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-2-(2- hydroxypropan-2-yl)- 4-methylthiazole-5- sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% IPA in Hex 453.1 178 202a or 202b

(S)-or (R)- 3-fluoro-N′-((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-4-(2- hydroxypropan-2- yl)benzenesulfonimidamide Chiral ART Cellulose- SB, 2*25 cm, 5 um 50% EtOH in Hex (8 mM NH₃• MeOH) 432.2 179 202b or 202a

(R)-or (S)- 3-fluoro-N′-((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-4-(2- hydroxypropan-2- yl)benzenesulfonimidamide Chiral ART Cellulose- SB, 2*25 cm, 5 um 50% EtOH in Hex (8 mM NH₃• MeOH) 432.2 180 116a or 116b

(S)-or (R)- N′-((8-fluoro-1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-4-(2- hydroxypropan-2-yl)-N- methylthiophene-2- sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% EtOH in Hex 452.1 181 116b or 116a

(R)-or (S)- N′-((8-fluoro-1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-4-(2- hydroxypropan-2-yl)-N- methylthiophene-2- sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% EtOH in Hex 452.1 182 173a or 173b

(S)-or (R)- N′-((4-cyano-2,6- diisopropylphenyl) carbamoyl)-3-fluoro-5- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 15% EtOH in Hex (0.1% DEA) 467.2 183 173b or 173a

(R)-or (S)- N′-((4-cyano-2,6- diisopropylphenyl) carbamoyl)-3-fluoro-5- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 15% EtOH in Hex (0.1% DEA) 467.2 184 174a or 174b

(S)-or (R)- 3-cyano-N′-((4-cyano-2,6- diisopropylphenyl) carbamoyl)-5-(2- hydroxypropan-2- yl) benzenesulfonimidamide ChiralPak IG, 2*25 cm, 5 um 15% EtOH in Hex (0.1% DEA) 468.2 185 174b or 174a

(R)-or (S)- 3-cyano-N′-((4-cyano-2,6- diisopropylphenyl) carbamoyl)-5-(2- hydroxypropan-2- yl) benzenesulfonimidamide ChiralPak IG, 2*25 cm, 5 um 15% EtOH in Hex (0.1% DEA) 468.2 186 223a or 223b

(S)-or (R)- N′-((4-cyano-2,6- diisopropylphenyl) carbamoyl)-5-(2- hydroxypropan-2-yl) thiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% EtOH in Hex (0.1% DEA) 449.2 187 223b or 223a

(R)-or (S)- N′-((4-cyano-2,6- diisopropylphenyl) carbamoyl)-5-(2- hydroxypropan-2-yl) thiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% EtOH in Hex (0.1% DEA) 449.2 188 158a or 158b

(S)-or (R)- N′-((4-cyano-2,6- diisopropylphenyl) carbamoyl)-3- (hydroxymethyl)-4-(2- hydroxypropan-2- yl) benzenesulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% EtOH in Hex (0.1% DEA) 473.2 189 158b or 158a

(R)-or (S)- N′-((4-cyano-2,6- diisopropylphenyl) carbamoyl)-3- (hydroxymethyl)-4-(2- hydroxypropan-2- yl) benzenesulfonimidamide ChiralPak ID, 2*25 cm, 5 um 30% EtOH in Hex (0.1% DEA) 473.2 190 220a or 220b

(S)-or (R)- N′-((8-cyano-1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl)-4- (hydroxymethyl)-2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide ChiralPak IF, 2*25 cm, 5 um MeOH (0.1% DEA) 476.1 191 220b or 220a

(R)-or (S)- N′-((8-cyano-1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl)-4- (hydroxymethyl)-2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide ChiralPak IF, 2*25 cm, 5 um MeOH (0.1% DEA) 476.1 192 157a or 157b

(S)-or (R)- N′-((4-cyano-2,6- diisopropylphenyl) carbamoyl)-4- (hydroxymethyl)-2- (2-hydroxypropan-2- yl)thiazole-5- sulfonimidamide ChiralPak IC, 2*25 cm, 5 um 15% EtOH in Hex 480.2 193 157b or 157a

(R)-or (S)- N′-((4-cyano-2,6- diisopropylphenyl) carbamoyl)-4- (hydroxymethyl)-2- (2-hydroxypropan-2- yl)thiazole-5- sulfonimidamide ChiralPak IC, 2*25 cm, 5 um 15% EtOH in Hex 480.2 194 161a or 161b

(S)-or (R)- N′-((4-cyano- 3-fluoro-2,6- diisopropylphenyl) carbamoyl)-4- (hydroxymethyl)-2- (2-hydroxypropan-2- yl)thiazole-5- sulfonimidamide ChiralPak IC, 2*25 cm, 5 um 15% EtOH in Hex 498.2 195 161b or 161a

(R)-or (S)- N′-((4-cyano- 3-fluoro-2,6- diisopropylphenyl) carbamoyl)-4- (hydroxymethyl)-2- (2-hydroxypropan-2- yl)thiazole-5- sulfonimidamide ChiralPak IC, 2*25 cm, 5 um 15% EtOH in Hex 498.2 196 165a or 165b

(S)-or (R)- N′-((4-cyano-2,6- diisopropylphenyl) carbamoyl)-4- (methylsulfonyl) benzenesulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% EtOH in Hex (0.1% DEA) 463.1 197 165b or 165a

(R)-or (S)- N′-((4-cyano-2,6- diisopropylphenyl) carbamoyl)-4- (methylsulfonyl) benzenesulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% EtOH in Hex (0.1% DEA) 463.1 198 172a or 172b

N′-((4-cyano-2,6- diisopropylphenyl) carbamoyl)-3,5-bis(2- hydroxypropan-2- yl)benzenesulfonimidamide ChiralPak IC, 2*25 cm, 5 um 15% EtOH in Hex (0.1% DEA) 501.2 199 172b or 172a

N′-((4-cyano-2,6- diisopropylphenyl) carbamoyl)-3,5-bis(2- hydroxypropan-2- yl)benzenesulfonimidamide ChiralPak IC, 2*25 cm, 5 um 15% EtOH in Hex (0.1% DEA) 501.2 200 106a or 106b

(R)-or (S)- N′-(8-fluoro-1,2,3,5,6,7- hexahydro-s- indacen-4- ylcarbamoyl)-2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide ChiralPak AD-H, 2*25 cm, 5 um 25% EtOH in CO2 439.2 201 106b or 106a

(S)-or (R)- N′-(8-fluoro-1,2,3,5,6,7- hexahydro-s- indacen-4- ylcarbamoyl)-2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide ChiralPak AD-H, 2*25 cm, 5 um 25% EtOH in CO₂ 439.2 202 136a or 136b

(S)-or (R)- N′-(1,2,3,5,6,7-hexahydro- s-indacen-4- ylcarbamoyl)-4-(2- hydroxypropan-2- yl)furan-2- sulfonimidamide Chiral ART Cellulose- SB, 2*25 cm, 5 um 20% EtOH in Hex (0.2% DEA) 404.2 203 136b or 136a

(R)-or (S)- N′-(1,2,3,5,6,7-hexahydro- s-indacen-4- ylcarbamoyl)-4-(2- hydroxypropan-2- yl)furan-2- sulfonimidamide Chiral ART Cellulose- SB, 2*25 cm, 5 um 20% EtOH in Hex (0.2% DEA) 404.2 204 183a or 183b

(R)-or (S)- N′-(1,2,3,5,6,7-hexahydro- s-indacen-4- ylcarbamoyl)-4-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 20% EtOH in Hex (0.1% DEA) 418.1 (M − 1) 205 183a or 183b

(S)-or (R)- N′-(1,2,3,5,6,7-hexahydro- s-indacen-4- ylcarbamoyl)-4-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide ChiralPak ID, 2*25 cm, 5 um 20% EtOH in Hex (0.1% DEA) 418.1 (M − 1) 206 176a or 176b

(S)-or (R)- N′-(8-fluoro-1,2,3,5,6,7- hexahydro-s- indacen-4- ylcarbamoyl)-4-(2- hydroxypropan-2-yl) thiophene-2- sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% EtOH in Hex 438.2 207 176b or 176a

(R)-or (S)- N′-(8-fluoro-1,2,3,5,6,7- hexahydro-s- indacen-4- ylcarbamoyl)-4-(2- hydroxypropan-2-yl) thiophene-2- sulfonimidamide ChiralPak IG, 2*25 cm, 5 um 30% EtOH in Hex 438.2 As a convention, the faster-eluting enantiomer is always listed first in the table followed by the slower-eluting enantiomer of the pair. The symbol * at a chiral center denotes that this chiral center has been resolved and the absolute stereochemistry at that center has not been determined.

Example 77 MS-ESI: 421.1 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (br s, 1H), 7.74 (br s, 2H), 7.68 (s, 1H), 6.87 (s, 1H), 5.36 (s, 1H), 3.02-2.50 (m, 8H), 2.10-1.80 (m, 4H), 1.48 (s, 6H). Example 200 MS-ESI: 439.2 (M+1). 1H NMR (400 MHz, DMSO-d₆) δ 8.38 (br, 1H), 8.02 (s, 1H), 7.75 (br, 1H), 6.27 (s, 1H), 2.81 (t, J=7.6 Hz, 4H), 2.70 (t, J=6.8 Hz, 4H), 2.02-1.95 (m, 4H), 1.50 (s, 6H). Example 203 MS-ESI: 404.2 (M+1). ¹H NMR (300 MHz, DMSO-d₆) δ 8.42 (br s, 1H), 7.76 (s, 1H), 7.72 (s, 2H), 7.01 (s, 1H), 6.88 (s, 1H), 5.11 (s, 1H), 2.90-2.72 (m, 4H), 2.72-2.60 (m, 4H), 2.10-1.80 (m, 4H), 1.46 (s, 6H). Example 205 MS-ESI: 418.1 (M−1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (br s, 1H), 7.68 (s, 2H), 7.63 (s, 1H), 7.59 (s, 1H), 6.88 (s, 1H), 5.23 (s, 1H), 2.95-2.75 (m, 4H), 2.75-2.60 (m, 4H), 2.05-1.80 (m, 4H), 1.43 (s, 6H). Example 206 MS-ESI: 438.2 (M+1). ¹H NMR (300 MHz, DMSO-d₆) δ 8.41 (br s, 1H), 7.65 (s, 2H), 7.59 (s, 1H), 7.55 (s, 1H), 5.20 (s, 1H), 2.90-2.60 (m, 8H), 2.10-1.80 (m, 4H), 1.39 (s, 6H). Example 208 (Compound 221)

4,5-Dichloro-N′-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)thiophene-2-sulfonimidamide

Step 1: N-(tert-butyldimethylsilyl)-4,5-dichlorothiophene-2-sulfonamide

4,5-Dichlorothiophene-2-sulfonamide (50 mg, 0.22 mmol) was dissolved in anhydrous CH₂Cl₂ (2 mL). Triethylamine (0.090 mL, 0.65 mmol) and TBSCl (38 mg, 0.25 mmol) were added and the resulting mixture was stirred overnight at room temperature, or until the reaction was complete as indicated by LCMS(Method F: m/Z=424.1 [M+DMSO+H]⁺, retention time=3.70 min). The reaction mixture was used in the next step as is.

Step 2: N-(tert-butyldimethylsilyl)-4,5-dichlorothiophene-2-sulfonimidamide

In an oven-dried vial under nitrogen, a solution of PPh₃Cl₂ (143 mg, 0.44 mmol) was prepared in dichloroethane (1.5 mL). Triethylamine (0.120 mL, 0.86 mmol) was introduced in a steady stream via syringe at 0° C. The reaction mixture was stirred at room temperature for 10 min. The reaction mixture was then cooled in an ice/water bath for 2 min and the reaction mixture of TBS protected sulfonamide (prepared in 2 mL DCM) from step 1 was introduced via syringe rapidly drop by drop (addition time <30 seconds). The resulting mixture was stirred at 0° C. for 30 min, at which time anhydrous ammonia was bubbled into the reaction mixture for 45 seconds. The suspension thus formed was stirred in an ice/water bath for 30 min and then warmed to room temperature and centrifuged to remove solids. The supernatant was concentrated in vacuo and dried under high vacuum for 30 min.

Step 3: 4,5-Dichloro-N′-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)thiophene-2-sulfonimidamide and N-(tert-butyldimethylsilyl)-4,5-dichloro-N′-((4-fluoro-2,6-diisopropyl phenyl)carbamoyl)thiophene-2-sulfonimidamide

To the crude reaction mixture from step 2 was added anhydrous THF (1.5 mL) and the resulting solution was stirred in an ice/water bath for 5 min, at which time NaH (17 mg, 0.44 mmol) was added. After 2 min stirring, a solution of 5-fluoro-2-isocyanato-1,3-diisopropylbenzene (36.5 mg, 0.165 mmol) in THF (3 ml) was added dropwise at 0° C. The resulting mixture was brought to room temperature and stirred for 30 min to give a mixture of crude products. LC-MS (Method F): m/Z=451.8 [M+H]⁺, retention time=6.18 min; for TBS-protected product, 566.4 [M+H]⁺, retention time=9.25 min.

Step 4: 4,5-Dichloro-N′-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)thiophene-2-sulfonimidamide

To the reaction mixture from step 3 was carefully added 4N HCl in dioxane (0.3 mL) and the resulting mixture was stirred at room temperature for approximately 30 min until the completion of reaction, as determined by LCMS analysis (Method F: 451.8 [M+H]⁺, retention time=6.18 min). The reaction mixture was then concentrated in vacuo. DMSO (0.5 mL) was added to the residue and the resulting solution was purified on a prep-HPLC to afford the title compound. LC-MS: 451 [M+H]⁺.

TABLE 20 Examples in the following table were prepared using similar procedures as described in Example 208 above starting from appropriate sulfonamides. Final Exact Ex. Target Mass # # Structure IUPAC Name [M + H]⁺ 209 219

N′-((4-fluoro-2,6-diisopropyl- phenyl)carbamoyl)-1,3- dimethyl-1H-pyrazole-4- sulfonimidamide 396.05 210 217

N′-((4-fluoro-2,6-diisopropyl- phenyl)carbamoyl)naphthalene- 2-sulfonimidamide 428.17 211 216

N′-((4-fluoro-2,6-diisopropyl- phenyl)carbamoyl)-2,3-dihydro- benzofuran-5-sulfonimidamide 420.07 212 215

N′-((4-fluoro-2,6-diisopropyl- phenyl)carbamoyl)-[1,1′- biphenyl]-2-sulfonimidamide 454.28 213 218

N′-((4-fluoro-2,6-diisopropyl- phenyl)carbamoyl)-2-(meth- oxymethyl)benzenesulfonimid- amide 422.17 214 214

2,5-dichloro-N′-((4-fluoro-2,6- diisopropylphenyl)carbamoyl)- thiophene-3-sulfonimidamide 452.18 215 211

N′-((4-fluoro-2,6-diisopropyl- phenyl)carbamoyl)pyridine-3- sulfonimidamide 379.24 216 210

N′-((4-fluoro-2,6-diisopropyl- phenyl)carbamoyl)benzo[d]- [1,3]dioxole-5-sulfonimidamide 422.17 217 201

N′-((4-fluoro-2,6-diisopropyl- phenyl)carbamoyl)-2,5-dimeth- ylfuran-3-sulfonimidamide 396.40 218 200

N′-((4-fluoro-2,6-diisopropyl- phenyl)carbamoyl)quinoline-3- sulfonimidamide 429.40 219 199

N′-((4-fluoro-2,6-diisopropyl- phenyl)carbamoyl)-6,7-dihydro- 5H-pyrrolo[1,2-a]imidazole-3- sulfonimidamide 408.40 220 198

N′-((4-fluoro-2,6-diisopropyl- phenyl)carbamoyl)-5-methyl- pyridine-2-sulfonimidamide 393.40

Example 221 (Compound 141)

N′-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide (Scheme 31)

Step 1: Phenyl (1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate

Into a 50-mL 3-necked round-bottom flask purged and maintained with nitrogen, was placed 1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine (50 mg, 0.29 mmol) in THF (10 mL), to this was added NaH (60% wt. oil dispersion, 22.8 mg, 0.57 mmol) at 0° C.; and then phenyl chloroformate (67.4 mg, 0.43 mmol,) in THF (2.0 mL) was added dropwise at 0° C. The resulting solution was stirred for 2 h at RT. This reaction solution was used for next step directly without any purification.

Step 2: N-(tert-butyldimethylsilyl)-N′-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide

Into a 50-mL 3-necked round-bottom flask purged and maintained with nitrogen, was placed N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonoimidamide (96 mg, 0.29 mmol) in THF (10 mL). To this was added NaH (60% wt. oil dispersion, 23.2 mg, 0.58 mmol) at 0° C., followed by phenyl (1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate (127 mg, 0.43 mmol) crude in THF from via syringe rapidly drop by drop. The resulting mixture was stirred for 16 h at RT. The reaction was then quenched by the addition of 5.0 mL of water. The resulting solution was extracted with 4×10 ml of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1;1). This resulted in 50 mg (38.4%) of the title compound as an off-white solid. MS-ESI: 533 (M+1).

Step 3: N′-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4-(2-hydroxypropan-2-yl) -5-methylfuran-2-sulfonimidamide

Into a 50-mL round-bottom flask, was placed N-(tert-butyldimethylsilyl)-N′-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylfuran-2-sulfonimidamide (58 mg, 0.11 mmol) in THF (10 mL), to this was added TBAF (28.8 mg, 0.11 mmol). The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with DCM/MeOH (10:1). The crude product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column 19*250 mm, 5 um; Mobile Phase A: water (10 mM NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 11% B to 40% B in 7 min; UV 254/210 nm; Rt: 6 min. This resulted in 25 mg (54.87%) of Example 221 as a white solid. MS-ESI: 419 (M+1). ¹H NMR (400 MHz, DMSO-d₆, ppm) δ: 8.82 (s, 1H), 7.65 (s, 2H), 6.90 (s, 1H), 5.03 (s, 1H), 2.82-2.78 (m, 4H), 2.76-2.67 (m, 4H), 2.41 (s, 3H), 2.00-1.92 (m, 4H), 1.39 (s, 6H).

TABLE 21 Examples in the following table were prepared using similar conditions as described in Example 221 and Scheme 31 from appropriate starting materials. Final Exact Ex. Target Mass # # Structure IUPAC Name [M + H]⁺ 222 140

N′-((3,5′-diisopropylpyridin-4- yl)carbamoyl)-4-(2-hydroxy- propan-2-yl)-5-methylfuran-2- sulfonimidamide 423

Example 223 (Compound 321)

2-(2-Hydroxypropan-2-yl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)thiazole-5-sulfonimidamide (Scheme 3A) Examples 224 and 225 (Compound 321b and 321a)

(R)- and (S)-2-(2-hydroxypropan-2-yl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)thiazole-5-sulfonimidamide

Route 1:

Step 1: Tert-butyl(2-(2-hydroxypropan-2-yl)-N-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl) carbamoyl)thiazole-5-sulfonimidoyl)carbamate

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-[amino[2-(2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]oxo-λ⁶-sulfanylidene]carbamate (1.39g, 4.32 mmol) in THF (50 mL). To this solution was added NaH (60% wt. oil dispersion, 518 mg, 13 mmol) at 0° C., followed by the addition of 3-isocyanato-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (800 mg, 4.32 mmol) in THF (5.0 mL) dropwise at 0° C. The resulting solution was stirred for 14 h at RT. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3×50 mL of DCM. The organic layers combined and dried over anhydrous Na₂SO₄, then concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:5 to 1:1). This resulted in 2.0 g (91%) of title compound as a light yellow solid. MS-ESI: 507 (M+1).

Step 2: 2-(2-Hydroxypropan-2-yl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl) thiazole-5-sulfonimidamide

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl(2-(2-hydroxypropan-2-yl)-N-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl) thiazole-5-sulfonimidoyl)carbamate (2.2 g, 4.34 mmol) in dioxane (40 mL). To this was added conc. HCl (8 mL,12 M) dropwise at 0° C. The resulting solution was stirred for 14 h at RT. The resulting solution was diluted with 100 mL of water. The resulting solution was extracted with 3×50 mL of DCM. The organic layers combined and dried over anhydrous Na₂SO₄, then concentrated. The crude product was purified by HP-Flash with the following conditions: Column, C18 silica gel; mobile phase, ACN:H₂O=25:75 increasing to ACN:H₂O=55:45 within 25; Detector, UV 254 nm. This resulted in 1.5 g (85%) of Example 223. MS-ESI: 407 (M+1). ¹H NMR (300 MHz, DMSO-d₆) δ 8.35 (s, 1H), 8.05 (s, 1H), 7.74 (s, 2H), 6.66 (s, 1H), 6.25 (s, 1H), 3.06-2.94 (m, 2H), 2.93-2.84 (m, 2H), 2.82-2.60 (m, 4H), 2.03-1.79 (m, 2H), 1.50 (s, 6H).

Step 3: Chiral Resolution

Example 223 (1.5 g) was separated with the followed condition: Column: CHIRALPAK IG, 20*250 mm, 5 um; Mobile Phase A: CO₂: 60, Mobile Phase B: MeOH—Preparative: 40; Flow rate: 50 mL/min; 220 nm. The resulting solution was stirred for 20 min at 10° C. This resulted in 546 mg (99% ee, 36.4%) of Example 224 (RT₁: 3.47 min) as a white solid and 595 mg (99% ee, 39.6%) of Example 225 (RT₂: 5.35 min) as a white solid. The absolute stereochemistry was tentatively assigned.

Example 224 MS-ESI: 407.1 (M+1). ¹H NMR (300 MHz, DMSO-d₆) δ 8.35 (s, 1H), 8.05 (s, 1H), 7.74 (s, 2H), 6.66 (s, 1H), 6.25 (s, 1H), 3.06-2.94 (m, 2H), 2.93-2.84 (m, 2H), 2.82-2.60 (m, 4H), 2.03-1.79 (m, 2H), 1.50 (s, 6H). Example 225 MS-ESI: 407.1 (M+1). ¹H NMR (300 MHz, DMSO-d₆) δ 8.35 (s, 1H), 8.05 (s, 1H), 7.74 (s, 2H), 6.66 (s, 1H), 6.25 (s, 1H), 3.06-2.94 (m, 2H), 2.93-2.84 (m, 2H), 2.82-2.60 (m, 4H), 2.03-1.79 (m, 2H), 1.50 (s, 6H).

Route 2:

Step 1: Chiral Resolution (R) and (S)-tert-butyl(amino(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ⁶-sulfaneylidene)carbamate

The product 10 g of Intermediate 28 was separated with the followed condition: Column: CHIRALPAK IC, 5*25 cm,5 um; Mobile Phase A:CO₂: 55, Mobile Phase B: EtOH:HeX=1:1:45; Flow rate: 150 mL/min; UV 220 nm; Rt₁: 5.13 (Intermediate 28A); Rt₂: 5.65 (Intermediate 28B). This resulted in 3 g (99.5% ee, 60%) of 28A, and 3 g (99.0% ee, 60%) of 28B.

Step 2: Tert-butyl (R)-(2-(2-hydroxypropan-2-yl)-N-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl) carbamoyl)thiazole-5-sulfonimidoyl)carbamate

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed intermediate 28A (>99% ee, 1.67 g, 5.20 mmol) in THF (50 mL), NaH (60% wt. oil dispersion, 624 mg, 15.6 mmol) was added at 0° C., this was followed by the addition of 3-isocyanato-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (850 mg, crude) in THF (5 mL) dropwise at 0° C. The resulting solution was stirred for 14 h at RT. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3×100 mL of DCM. The organic layers combined and dried over anhydrous Na₂SO₄, then concentrated. This resulted in 2.2 g (83.5%) of title compound as a light yellow solid. MS-ESI: 507 (M+1).

Step 3: (R)-2-(2-hydroxypropan-2-yl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl) thiazole-5-sulfonimidamide

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (S)-(2-(2-hydroxypropan-2-yl)-N-((2,4,5,6-tetrahydro-1H-cyclobuta[f] inden-3-yl)carbamoyl) thiazole-5-sulfonimidoyl)carbamate (2.2 g, 4.34 mmol) in dioxane (40 mL), to this was added conc. HCl (8 mL, 12M) dropwise at 0° C. The resulting solution was stirred for 8 h below 10° C. The resulting solution was diluted with 100 mL of water. The resulting solution was extracted with 3×100 mL of DCM. The organic layers combined and dried over anhydrous Na₂SO₄, then concentrated. The crude product was purified by HP-Flash with the following conditions: Column, C18 silica gel; mobile phase, MeCN:water=25:75 increasing to MeCN:water=55:45 within 30 min; Detector, UV 210 nm. This resulted in 1.37 g (77.3%) of Example 224 (99.4% ee) as a white solid. MS-ESI: 407 (M+1).

¹H NMR (300 MHz, DMSO-d₆) δ 8.43 (s, 1H), 8.09 (s, 1H), 7.90 (s, 2H), 6.67 (s, 1H), 6.29 (s, 1H), 2.92 (d, J=3.9 Hz, 2H), 2.89 (d, J=3.9 Hz, 2H), 2.90-2.55 (m, 4H), 2.00-1.75 (m, 6H), 1.50 (s, 6H).

TABLE 22 Examples in the following table were prepared using similar conditions as described in Example 223- Route 1 and Scheme 3A from appropriate starting materials. Final Exact Ex. Target Mass # # Structure IUPAC Name [M + H]⁺ 226 329

2-(2-Hydroxypropan-2-yl)- N′-(tricyclo[6.2.0.03,6]deca- 1,3(6),7-trien-2-ylcarbam- oyl)thiazole-5-sulfonimid- amide 393 227 375

N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl-3,3,5,5-d₄)- carbamoyl)-2-(2-hydroxy- propan-2-yl)thiazole-5- sulfonimidamide 425 228 376

N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl-1,1,7,7-d₄)- carbamoyl)-2-(2-hydroxy- propan-2-yl)thiazole-5- sulfonimidamide 425

Example 229 (Compound 307)

2-Fluoro-N′-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-hydroxybenzenesulfonimidamide (Scheme 3B)

Step 1: N-(tert-butyldimethylsilyl)-2-fluoro-N′-(8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-methoxybenzenesulfonimidamide

Into a 50-mL round-bottom flask, was placed a solution of N-(tert-butyldimethylsilyl)-2-fluoro-4-methoxybenzene-1-sulfonoimidamide (139 mg, 0.44 mmol) in THF (5.0 mL). To this solution was added NaH (60% wt. oil dispersion, 35.2 mg, 0.44 mmol) at 0° C. This was followed by the addition of 4-fluoro-8-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (95 mg, 0.44 mmol) in THF (5 mL) dropwise at RT. The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3×50 mL of ethyl acetate. The organic layers combined and dried over anhydrous Na₂SO₄, and then concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:5 to 1:1). This resulted in 120 mg (51.2%) of the title compound as yellow oil. MS-ESI: 536 (M+1).

Step 2: 2-Fluoro-N′-(8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-hydroxybenzenesulfonimidamide

Into a 50-mL round-bottom flask, was placed a solution of 1-[[(tert-butyldimethylsilyl)imino](2-fluoro-4-methoxybenzene)sulfinyl]-3-(8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea (120 mg, 0.22 mmol) in ACN (5.0 mL), to this solution was added BBr₃ (561 mg, 2.24 mmol) dropwise at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 5 mL of MeOH. The resulting mixture was concentrated. The crude product (100 mg) was purified by Prep-HPLC under the following conditions: Column, XBridge Prep OBD C18, 19*250 mm, 5 um; mobile phase: water (10 mM NH₄HCO₃) and ACN (25% to 43% ACN gradient in 7 min); Detector, UV. This resulted in 17.7 mg (19.4%) of Example 229 as a white solid. MS-ESI: 408 (M+1).

Example 230 (Compound 323)

N′-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (Scheme 32)

Into a 50-mL round-bottom flask, was placed 2-(2-hydroxypropan-2-yl)-N′-((1-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiazole-5-sulfonimidamide (100 mg, 0.23 mmol) in ethanol (10 mL). To this solution was added NaBH₄ (17.4 mg, 0.46 mmol) in portions at 0° C. The resulting solution was stirred for 2 h at RT. The crude product (5 mL) was purified by Flash-Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column 30×150 mm 5 um; Mobile Phase A: water (10 mM NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% to 28% B in 7 min; 210/254 nm; Rt: 6.00 min. This resulted in 180 mg of the title compound (Example 230) as a solid. MS-ESI: 437.1 (M+1).

¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (br s, 1H), 8.04 (s, 1H), 7.82 (br s, 2H), 6.97 (s, 1H), 6.28 (s, 1H), 5.07 (d, J=5.6 Hz, 1H), 5.05-4.85 (m, 1H),2.95-2.75 (m, 2H), 2.75-50 (m, 4H), 2.35-2.15 (m, 1H), 2.00-1.80 (m, 2H), 1.80-1.60 (m, 1H), 1.51 (s, 6H).

Example 231 (Compound 338)

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-((3-methoxyazetidin-1-yl)methyl)benzenesulfonimidamide (Scheme 33A)

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1-[amino[4-(bromomethyl)phenyl]oxo-λ⁶-sulfanylidene]-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea(50 mg, 0.11 mmol) in THF(5 mL). To this solution was added DIEA (28.4 mg, 0.22 mmol) and 3-methoxyazetidine(10.5 mg, 0.12 mmol) at RT. The resulting solution was stirred for 1 h at 65° C. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19×100 mm 5 um 13 nm; Mobile Phase A: water (10 mM NH₄HCO₃ mM+0.1% NH₃H₂O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 30% to 37% B in 9.5 min; 254/210 nm; Rt: 9.62 min. This resulted in 5 mg of Example 231 as a white solid. MS-ESI: 455 (M+1). ¹H NMR (300 MHz, DMSO-d₆) δ: 8.27 (br s, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.34 (s, 2H), 6.85 (s, 1H), 4.02-3.94 (m, 1H), 3.67 (s, 2H), 3.51-3.46 (m, 2H), 3.14(s, 3H), 2.95-2.80 (m, 2H), 2.78-2.73 (m, 4H), 2.69-2.63 (m, 4H), 1.96-1.88 (m, 4H).

TABLE 23 Examples in the following table were prepared using similar conditions as described in Example 231 and Scheme 33A from appropriate starting materials. Final Exact Ex. Target Mass # # Structure IUPAC Name [M + H]⁺ 232 341

N′-(1,2,3,5,6,7-hexahydro- s-indacen-4-ylcarbamoyl)- 4-(((2-methoxyethyl)- (methyl)amino)methyl)- benzenesulfonimidamide 457 233 342

N′-(1,2,3,5,6,7-hexahydro- s-indacen-4-ylcarbamoyl)- 4-(hydroxymethyl)- benzenesulfonimidamide 386 234 345

N′-(1,2,3,5,6,7-hexahydro- s-indacen-4-ylcarbamoyl)- 4-(morpholinomethyl)- benzenesulfonimidamide 455 235 346

4-((3,3-Difluoropyrrol- idin-1-yl)methyl)-N′- (1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)- benzenesulfonimidamide 475 236 347

N′-(1,2,3,5,6,7-hexahydro- s-indacen-4-ylcarbamoyl)- 4-(pyrrolidin-1-ylmethyl)- benzenesulfonimidamide 439 237 348

4-(Azetidin-1-ylmethyl)- N′-(1,2,3,5,6,7-hexahydro- s-indacen-4-ylcarbamoyl)- benzenesulfonimidamide 425 238 403

4-((Allyl(methyl)amino)- methyl)-N′-(1,2,3,5,6,7- hexahydro-s-indacen-4- ylcarbamoyl)benzene- sulfonimidamide 439 239 402

N′-(1,2,3,5,6,7-hexahydro- s-indacen-4-ylcarbamoyl)- 4-((methyl(prop-2-ynyl)- amino)methyl)benzene- sulfonimidamide 437 240 350

4-(((Cyclopropylmethyl)- (methyl)amino)methyl)- N′-(1,2,3,5,6,7-hexahydro- s-indacen-4-ylcarbamoyl)- benzenesulfonimidamide 453 241 322

4-(((2,2-Difluoroethyl)- (methyl)amino)methyl)- N′-(1,2,3,5,6,7-hexahydro- s-indacen-4-ylcarbamoyl)- benzenesulfonimidamide 463 242 351

N′-(1,2,3,5,6,7-hexahydro- s-indacen-4-ylcarbamoyl)- 4-(methoxymethyl)- benzenesulfonimidamide 400 243 358

4-(Aminomethyl)-N′- (1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)- benzenesulfonimidamide 385

Example 244 (Compound 401)

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-((2-oxopyrrolidin-1-yl)methyl)benzenesulfonimidamide (Scheme 33B)

Into a 40-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 1-[amino[4-(bromomethyl)phenyl]oxo-λ⁶-sulfanylidene]-3-(1,2,3,5, 6,7-hexahydro-s-indacen-4-yl)urea (200 mg, 0.45 mmol) in THF (10 mL), to this stirred solution was added DIEA (173 mg, 1.34 mmol) and pyrrolidin-2-one (114 mg, 1.34 mmol) at RT. The resulting solution was stirred for 3 h at 60° C. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Prep OBD C18, 30×150 mm 5 um; mobile phase, water (10 mM NH₄HCO₃) and ACN (25% to 44% ACN gradient in 7 min); Detector, UV. This resulted in 10 mg (4.95%) of Example 244 as a white solid. MS-ESI: 453 (M+1).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.26 (br s, 1H), 7.83 (d, J=8.0 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 7.27 (br s, 2H), 6.85 (s, 1H), 4.43 (s, 2H), 3.26-3.22 (m, 2H), 2.78-2.74 (m, 4H), 2.65-2.61 (m, 4H), 2.30 (t, J=8.20 Hz, 2H), 1.98-1.89 (m, 6H).

Example 245 (Compound 404)

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)-N,N-dimethylthiophene-2-sulfonimidamide (Scheme 4A)

Into a 50-mL 3-necked round-bottom flask, was placed a solution of 4-(2-hydroxypropan-2-yl)-N,N-dimethylthiophene-2-sulfonoimidamide (125 mg, 0.50 mmol) in THF (2.0 mL). To this was added NaH (60% wt. oil dispersion, 30.2 mg, 0.75 mmol) in several batches at 0° C. in an ice/water bath. To the mixture was added 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (110 mg, 0.55 mmol) at 0° C. in an ice/water bath. The resulting solution was stirred for 30 min at 0° C. in a water/ice bath. The reaction was then quenched by the addition of NH₄Cl (aq.). The resulting solution was extracted with ethyl acetate and the organic layers combined, the organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: X Bridge Prep C₁₈ OBD, 19*150 mm 5 um; mobile phase, water (10 mM NH₄HCO₃) and ACN (10% to 80% in 6 min); Detector, UV 254 nm. This resulted in 90 mg (39.9%) of Example 245 as a white powder. MS-ESI: 448.2 (M+1). ¹H NMR (DMSO-d₆, 300 MHz): δ 8.60 (br s, 1H), 7.71 (s, 1H), 7.58 (br s, 1H), 6.88 (s, 1H), 5.21 (s, 1H), 2.86-2.70 (m, 8H), 2.70 (s, 6H), 1.98-1.90 (m, 4H), 1.3 (s, 6H).

Example 246 (Compound 331)

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)-N-methylthiophene-2-sulfonimidamide (Scheme 4)

Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-(2-hydroxypropan-2-yl)-N-methylthiophene-2-sulfonoimidamide (106 mg, 0.45 mmol) in THF (4.0 mL). This was followed by the addition of NaH (60% wt. oil dispersion, 23.5 mg, 0.59 mmol) in several batches at 0° C. in a water/ice bath. To this was added a solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (99.1 mg, 0.50 mmol) in THF (2.0 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 30 min at 0° C. in a water/ice bath. The reaction was then quenched by the addition of water/ice. The resulting solution was extracted with ethyl acetate and the organic layers combined, the organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Column, X Bridge Shield RP18 OBD, 19×250 mm, 10 um; mobile phase, water (10 mM NH₄HCO₃+0.1% NH₃.H₂O) and ACN (43% to 67% ACN gradient in 6 min); Detector, UV 254 nm. This resulted in 80 mg (40.79%) of Example 246 as a white solid. MS-ESI: 434.15 (M+1). ¹H NMR (DMSO-d₆, 300 MHz): δ 8.55 (br s, 1H) 7.65 (s, 1H), 7.59 (s, 1H), 7.53 (s, 1H), 6.89 (s, 1H), 5.22 (s, 1H) 2.63-2.85 (m, 8H) 2.49 (s, 3H) 2.00-1.80 (m, 4H) 1.31 (s, 6H).

TABLE 24 Examples in the following table were prepared using similar conditions as described in Example 246 and Scheme 4 from appropriate starting materials. Final Exact Example Target Mass # Number Structure IUPAC Name [M + H]⁺ 247 339

N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)- 2-(2-hydroxypropan-2-yl)- N-methylthiazole-5-sulfon- imidamide 435

Example 248 (Compound 405)

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)(methyl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (Scheme 34)

Step 1: Tert-butyl(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)(methyl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidoyl)carbamate

Into a 50-mL round-bottom flask, was placed tert-butyl N-([[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl]imino][2-(2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]oxo-λ⁶-sulfanyl)carbamate (200 mg, 0.38 mmol) in THF (10 mL), to this stirred solution was added CH₃I (60 mg, 0.42 mmol) dropwise at 0° C. The resulting solution was stirred for 1 d at RT. The resulting mixture was concentrated. This resulted in 100 mg (49%) of the title compound as a solid. MS-ESI: 535 (M+1).

Step 2: N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)(methyl)carbamoyl)-2-(2-hydroxypropan-2-yl) thiazole-5-sulfonimidamide

Into a 25-mL round-bottom flask, was placed tert-butyl N-([[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl) (methyl)carbamoyl]imino][2-(2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]oxo-λ⁶-sulfanyl)carbamate (100 mg) in HCl (4M, 10 mL). The resulting solution was stirred for 5 h at RT. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD, 5 um, 19*150 mm; mobile phase, water (10 mM NH₄HCO₃ mM) and ACN (22% to 53% ACN gradient in 7 min); Detector, UV. This resulted in 15.7 mg of Example 248 as a solid. MS-ESI: 435 (M+1).

TABLE 25 Example 249 was isolated as a side product from the preparation of Example 248. Final Exact Example Target Mass # Number Structure IUPAC Name [M + H]⁺ 249 406

N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)(methyl)- carbamoyl)-2-(2-hydroxy- propan-2-yl)-N-methyl- thiazole-5-sulfonimidamide 449

Example 250 (Compound 324)

N-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidoyl)acetamide (Scheme 35A)

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (200 mg, 0.48 mmol) and TEA (96 mg, 0.96 mmol) in DCM (20 mL). To the stirred solution, Ac₂O (74 mg, 0.72 mmol) was added dropwise at 0° C. The resulting solution was stirred overnight. Then 80 mg of the product was obtained by Prep-HPLC with the following conditions: Column: XBridge Prep C18 OBD Column 19×150 mm 5 um; Mobile Phase A: water (10 mM NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 18% B to 41% B in 7 min; 254/210 nm; Rt: 5.05 min, this resulted in 100 mg of the Example 250 as a white solid. MS-ESI: 462.14 (M+1). ¹H NMR (300 MHz, CD3OD-d₄) δ: 8.11 (s, 1H), 6.89 (s, 1H), 2.92-2.69 (m, 8H), 2.09-2.01 (m, 4H), 1.99 (s, 3H), 1.60 (d, J=2.3 Hz, 6H).

Example 251 (Compound 407)

methyl 4-((4-(N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)benzyl)(methyl)amino)-4-oxobutanoate (Scheme 35)

Into a 8-mL round-bottom flask, was placed a solution of 1-[amino([4-[(methylamino)methyl]-phenyl])oxo-λ⁶-sulfanylidene]-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea (100 mg, 0.25 mmol), methyl 4-chloro-4-oxobutanoate (37.8 mg, 0.25 mmol) in DMF (10 mL), to this stirred solution was added HATU (191 mg, 0.50 mmol) and DIEA (64.9 mg, 0.50 mmol). The resulting solution was stirred for 20 min at RT. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD, 19*250 mm,10 um; mobile phase, water (10 mM NH₄HCO₃) and ACN (15% to 75% ACN gradient in 7 min); Detector, UV 250 nm. This resulted in 4.2 mg (3.27%) of Example 251 as a white solid. MS-ESI: 513 (M+1). ¹H NMR (300 MHz, CD3OD-d₄) δ: 8.02-7.94 (m, 2H), 7.49-7.41 (m, 2H), 6.89 (s, 1H), 4.68 (s, 2H), 3.68 (s, 3H), 3.04 (s, 3H), 2.85-2.80 (m, 4H), 2.75-2.60 (m, 8H), 2.03-1.97 (m, 4H).

Example 252 (Compound 410)

4-((4-(N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)sulfamimidoyl)benzyl)(methyl)amino)-4-oxobutanoic acid

Into a 50-mL round-bottom flask, was placed a solution of methyl 3-[([4-[amino([[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]imino])oxo-λ⁶-sulfanyl]phenyl]methyl)(methyl)-carbamoyl]propanoate (80 mg, 0.16 mmol) in THF (3.0 mL) and H₂O (3.0 mL), to the stirred solution was added KOH (17.5 mg, 0.31 mmol). The resulting solution was stirred for 120 min at RT. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD, 19*250 mm,10 um; mobile phase, water (10 mM NH₄HCO₃) and ACN (15% to 75% gradient in 7 min); Detector, UV250 nm. This resulted in 39 mg (50%) of Example 252 as a white solid. MS-ESI: 499 (M+1). ¹H-NMR (300 MHz, CD₃OD-d₄) δ: 8.10-7.80 (m, 2H), 7.55-7.30 (m, 2H), 6.89 (s, 1H), 4.68 (s, 2H), 3.04 (s, 3H), 2.90-2.60 (m, 12H), 2.10-1.80 (m, 4H).

Example 253 (Compound 408)

(E)-N-(4-(N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)benzyl)-N-methyloct-4-en-7-ynamide (Scheme 35)

Example 253 was prepared using similar conditions as described in Example 251 and Scheme 35 from 3-(3-(but-3-ynyl)-3H-diazirin-3-yl)propanoic acid and Intermediate 67. MS-ESI: 519 (M+1)

TABLE 26 Examples in the following table were prepared using similar conditions as described in Example 4 - route 1 and Scheme 2 from appropriate starting materials. Final Exact Example Target Mass # Number Structure IUPAC Name [M + H]⁺ 254 308

N′-((3-cyano-2,6-diisopropyl- phenyl)carbamoyl)-5-(2- hydroxypropan-2-yl)thio- phene-2-sulfonimidamide 449 255 311

N′-((6-ethyl-1-methyl-1H- indazol-7-yl)carbamoyl)-5- (2-hydroxypropan-2-yl)- thiazole-2-sulfonimidamide 423 256 312

N′-((6-ethyl-2-methyl-2H- indazol-7-yl)carbamoyl)-5- (2-hydroxypropan-2-yl)- thiazole-2-sulfonimidamide 423 257 327

5-(2-hydroxypropan-2-yl)- N′-((3,5,6,7-tetrahydro-2H- indeno[5,6-b]furan-4-yl)- carbamoyl)thiazole-2-sulfon- imidamide 423 258 326

5-(2-Hydroxypropan-2-yl)- N′-((3,5,6,7-tetrahydro-2H- indeno[5,6-b]furan-8-yl)- carbamoyl)thiazole-2- sulfonimidamide 423 259 139

N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)- 5-(2-hydroxypropan-2-yl)- 1-phenyl-1H-pyrazole-3- sulfonimidamide 480 260 137

N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)- 6-(2-hydroxypropan-2-yl)- pyridine-3-sulfonimidamide 415 261 409

N-(4-(N′-((1,2,3,5,6,7-hexa- hydro-s-indacen-4-yl)car- bamoyl)sulfamidimidoyl)- benzyl)-N-methylpent-4- ynamide 479 262 303

4-(2-Hydroxypropan-2-yl)- N′-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3-yl)car- bamoyl)thiazole-2-sulfon- imidamide 407 263 325

4-(2-Hydroxypropan-2-yl)- N′-((3,5,6,7-tetrahydro-2H- indeno[5,6-b]furan-8-yl)- carbamoyl)thiazole-2-sulfon- imidamide 423 264 138

N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)- 6-(2-hydroxypropan-2-yl)-2- methylpyridine-3-sulfon- imidamide 429 265 332

N′-(1,2,3,5,6,7-hexahydro- s-indacen-4-ylcarbamoyl)-4- (2-hydroxypropan-2-yl)-5- methylthiazole-2-sulfon- imidamide 435 266 334

4-(1-(Dimethylamino)ethyl)- N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)- benzenesulfonimidamide 427 267 335

4-(2-(Dimethylamino)- propan-2-yl)-N′-(1,2,3,5,6,7- hexahydro-s-indacen-4-yl- carbamoyl)benzenesulfon- imidamide 441 268 337

N-(4-(N′-(1,2,3,5,6,7-hexa- hydro-s-indacen-4-ylcar- bamoyl)sulfamimidoyl)- benzyl)-N-methylacetamide 441 269 113

3-Fluoro-N′-(1,2,3,5,6,7- hexahydro-s-indacen-4- ylcarbamoyl)-5-(2-hydroxy- propan-2-yl)thiophene-2- sulfonimidamide 438 270 343

N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)- 2-methyl-1,2,3,4-tetrahydro- isoquinoline-6-sulfonimid- amide 425 271 349

N-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-2- methyl-1,2,3,4-tetrahydro- isoquinoline-7-sulfonimid- amide 425 272 344

4-((Dimethylamino)methyl)- N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)- 2-methoxybenzenesulfon- imidamide 443 273 359

N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-1- methyl-1H-indazole-5- sulfonimidamide 410 274 352

N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-4- (2-methoxypropan-2-yl)- benzenesulfonimidamide 428 275 354

N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-6- isobutylpyridine-3-sulfon- imidamide 413 276 355

6-((Dimethylamino)methyl)- N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)- pyridine-3-sulfonimidamide 414 277 356

N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)-4- isobutylbenzenesulfonimid- amide 412 278 357

5-((Dimethylamino)methyl)- N′-(1,2,3,5,6,7-hexahydro-s- indacen-4-ylcarbamoyl)- pyridine-2-sulfonimidamide 414 279 340

5-((Dimethylamino)methyl)- 3-fluoro-N′-(1,2,3,5,6,7- hexahydro-s-indacen-4-yl- carbamoyl)thiophene-2- sulfonimidamide 437 280 377

4-((dimethylamino)methyl)- 3-fluoro-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)- carbamoyl)benzenesulfon- imidamide 431 281 378

3-fluoro-5-(2-hydroxypro- pan-2-yl)-N′-((2,4,5,6-tetra- hydro-1H-cyclobuta[f]inden- 3-yl)carbamoyl)thiophene- 2-sulfonimidamide 424 282 379

N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)- 4-isopropylthiophene-2- sulfonimidamide 404 283 380

N-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)- 4-(1-methylpyrrolidin-2- yl)benzenesulfonimidamide 439 284 353

N′-((3,5-diisopropyl-1- phenyl-1H-pyrazol-4-yl)car- bamoyl)-4-(2-hydroxypro- pan-2-yl)thiophene-2-sulfon- imidamide 490 285 333

N′-((1,2,3,6,7,8-hexahydro- as-indacen-4-yl)carbamoyl)- 2-(2-hydroxypropan-2-yl)- thiazole-5-sulfonimidamide 421 287 382

2-fluoro-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-4-((methyl- amino)methyl)benzene- sulfonimidamide 417 288 383

N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)- 6-isopropylpyridine-3- sulfonimidamide 399

TABLE 27 Examples in the following table were prepared using similar conditions as described in Example 4 - route 2 and Scheme 3 from appropriate starting materials. Final Exact Example Target Mass # Number Structure IUPAC Name [M + H]⁺ 289 315

2-(2-Hydroxypropan-2-yl)- N′-((3,5,6,7-tetrahydro-2H- indeno[5,6-b]furan-8-yl)- carbamoyl)thiazole-5-sulfon- imidamide 423 290 316

N′-((6-ethyl-1H-indazol-7- yl)carbamoyl)-2-(2-hydroxy- propan-2-yl)thiazole-5- sulfonimidamide 409 291 317

2-(2-Hydroxypropan-2-yl)- N′-((1-methyl-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)- carbamoyl)thiazole-5-sulfon- imidamide 435 292 319

2-(2-Hydroxypropan-2-yl)- N′-((3-methyl-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)- carbamoyl)thiazole-5-sulfon- imidamide 435 293 320

2-(2-Hydroxypropan-2-yl)- N′-((1-oxo-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)- carbamoyl)thiazole-5-sulfon- imidamide 435 294 336

2-(2-Hydroxypropan-2-yl)- N′-((3-oxo-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)- carbamoyl)thiazole-5-sulfon- imidamide 435 295 330

N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)- 2-(2-methoxypropan-2-yl)- thiazole-5-sulfonimidamide 435

TABLE 28 Examples in the following table were obtained from chiral HPLC resolutions of racemic examples described above. The chiral column and eluents are listed in the table. As a convention, the faster-eluting enantiomer is always listed first in the table followed by the slower-eluting enantiomer of the pair. The symbol * at a chiral center denotes that this chiral center has been resolved and the absolute stereochemistry at that center has not been determined. For mixtures contained two chiral centers and if two columns are used for separating the four diastereomers, the individual isomers are listed in the order of faster column 1/faster column 2; faster column 1/slower column 2; slower column 1/faster column 2; followed by slower column 1/slower column 2. Final Ex. Target LC-MS # Number Structure IUPAC Name Column Eluents [M + H]⁺ 296 364a

(R) or (S)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)- carbamoyl)-5-(2-hydroxy- propan-2-yl)-thiazole-2- sulfonimidamide CHIRALPAK IG 2*25 cm (5 um) 50% MeOH (8 mM NH₃- MeOH) in CO₂ ^(#) 421 297 364b

(S) or (R)-N′-((1,2,3,5.6,7- hexahydro-s-indacen-4-yl)- carbamoyl)-5-(2-hydroxy- propan-2-yl)thiazole-2- sulfonimidamide CHIRALPAK IG 2*25 cm (5 um) 50% MeOH (8 mM NH₃• MeOH) in CO₂ 421 298 365a

(R) or (S)-N′-((3-fluoro- 2,6-diisopropylphenyl)- carbamoyl)-2-(2-hydroxy- propan-2-yl)thiazole-5- sulfonimidamide Chiralpak ID, 2*25 cm, 5 um IPA in Hex: DCM = 5:1 443 299 365b

(S) or (R)-N′-((3-fluoro- 2,6-diisopropylphenyl)- carbamoyl)-2-(2-hydroxy- propan-2-yl)thiazole-5- sulfonimidamide Chiralpak ID, 2*25 cm, 5 um IPA in Hex: DCM = 5:1 443 300 308a

(R) or (S)-N′-((3-cyano- 2,6-diisopropylphenyl)- carbamoyl)-5-(2-hydroxy- propan-2-yl)thiophene-2- sulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um 30% EtOH in Hex (0.1% DEA) 449 301 308b

(S) or (R)-N′-((3-fluoro- 2,6-diisopropylphenyl)- carbamoyl)-2-(2-hydroxy- propan-2-yl)thiazole-5- sulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um 30% EtOH in Hex (0.1% DEA) 449 126 195a

Two isomers of (S, S)- and (S, R)-or (R, S)-and (R, R) 4-(2-hydroxypro- pan-2-yl)-5-methyl-N′- ((3-methyl-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)furan-2- sulfonimidamide CHIRALART Cellulose- SB, 2*25 cm, 5 um MeOH (0.1% DEA); 1^(st) and 2^(nd) peaks 432 127 195e

Two isomers of (R, S)-and (R, R)-or (S, S)-and (S, R) 4-(2-hydro xypropan-2- yl)-5-methyl-N′-((3-meth- yl-1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)- furan-2-sulfonimidamide MeOH (0.1% DEA); 3^(rd) peak 432 302  195ba

(R, R) or (R, S) or (S, S) or (S, R)-4-(2-hydroxy- propan-2-yl)-5-methyl-N′- ((3-methyl-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)- carbamoyl)furan-2-sulfon- imidamide resolved from example 127 Phenomene × Lux 5u Cellulose-4, AXIA Packed 2.12*25 cm, 5 um 40% MeOH in CO₂ 432 303  195bb

(R, S) or (R, R) or (S, R) or (S, S)-4-(2-hydroxy- propan-2-yl)-5-methyl-N′- ((3-methyl-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)- carbamoyl)furan-2-sulfon- imidamide resolved from example 127 Phenomene × Lux 5u Cellulose-4, AXIA Packed 2.12*25 cm, 5 um 40% MeOH in CO₂ 432 123 207c

Two isomers of (R, S)-and (R, R) 4-(2-hydroxypropan- 2-yl)-5-methyl-N′-(1-meth- yl-1,2,3,5,6,7-hexahydros- indacen-4-ylcarbamoyl)- furan-2-sulfonimidamide ChiralPak IC, 2*25cm, 5um 50% EtOH in MTBE; 1^(st) and 2^(nd) peaks  432.2 124  207aa

(S, S)-or (S, R)-4-(2- hydroxypropan-2-yl)-5- methyl-N′-(1-methyl- 1,2,3,5,6,7-hexahydros- indacen-4-ylcarbamoyl)- furan-2-sulfonimidamide 50% EtOH in MTBE; 3^(rd) peak  432.2 125 207b

(S, R)-or (S, S)-4-(2- hydroxypropan-2-yl)-5- methyl-N′-(1-methyl- 1,2,3,5,6,7-hexahydros- indacen-4-ylcarbamoyl)- furan-2-sulfonimidamide 50% EtOH in MTBE; 4^(th) peak  432.2 304 207a

(R, R) or (R, S)-4-(2- hydroxypropan-2-yl)-5- methyl-N′-((3-methyl- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- furan-2-sulfonimidamide; resolved from example 123 CHIRALPAK IG, 20*250 mm, 5 um EtOH in Hex (0.1% FA) 432 305  207bb

(R, S) or (R, R)-4-(2- hydroxypropan-2-yl)-5- methyl-N′-((3-methyl- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- furan-2-sulfonimidamide; resolved from example 123 CHIRALPAK IG, 20*250 mm, 5 um EtOH in Hex (0.1% FA) 432 306 366a

(R) or (S)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-4-(2- hydroxypropan-2-yl)- thiazole-2-sulfonimidamide CHIRALPAK AS-H, 2*25 cm (5 um) 35% IPA (2 mM NH₃- MeOH) in CO₂ 421 307 366b

(S) or (R)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)- carbamoyl)-4-(2-hydroxy- propan-2-yl)thiazole-2- sulfonimidamide CHIRALPAK AS-H, 2*25 cm (5 um) 35% IPA (2 mM NH₃- MeOH) in CO₂ 421 308 139a

(S) or (R)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-5-(2- hydroxypropan-2-yl)-1- phenyl-1H-pyrazole-3- sulfonimidamide CHIRALPAK AS-H, 2*25 cm (5 um) EtOH in Hex (0.1% DEA) 480 309 139b

(R) or (S)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-5-(2- hydroxypropan-2-yl)-1- phenyl-1H-pyrazole-3- sulfonimidamide CHIRALPAK AS-H, 2*25 cm (5 um) EtOH in Hex (0.1% DEA) 480 310 367a

(R) or (S)-N′-((8-fluoro- 1,2,3,5,6,7-hcxahydro-s- indacen-4-yl)carbamoyl)- 4-(2-hydroxypropan-2- yl)thiazole-2-sulfonimid- amide Chiralpak AS-H 2*25 cm (5 um) 35% IPA in CO₂ 439 311 367b

(S) or (R)-N′-((8-fluoro- 1,2,3,5,6,7-hcxahydro-s- indacen-4-yl)carbamoyl)- 4-(2-hydroxypropan-2- yl)thiazole-2-sulfonimid- amide Chiralpak AS-H 2*25 cm (5 um) 35% IPA in CO₂ 439 312 409b

(S) or (R)-N-(4-(N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- sulfamidimidoyl)benzyl)- N-methylpent-4-ynamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 479 313 409a

(R) or (S)-N-(4-(N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- sulfamidimidoyl)benzyl)- N-methylpent-4-ynamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃• MeOH) 479 314 369a

(S) or (R)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-4-((methyl- amino)methyl)benzene- sulfonimidamide Chiralpak ID-2, 2*25 cm, 5 um EtOH in Hex (8 mM NH3• MeOH) 399 315 369b

(R) or (S)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-4-((methyl- amino)methyl)benzene- sulfonimidamide Chiralpak ID-2, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃• MeOH) 399 316 159a

Two isomers of (R, R) or (R, S) or (S, S) or (S, R)- N′-((4-cyano-3-fluoro-2,6- diisopropylphenyl)carbam- oyl)-2-(1,2-dihydroxypro- pan-2-yl)-thiazole-5- sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 1^(st) and 2^(nd) peak 484 317  159ab

(R, R) or (R, S) or (S, S) or (S, R)-N-((4-cyano-3- fluoro-2,6-diisopropyl- phenyl)carbamoyl)-2-(1,2- dihydroxypropan-2-yl)- thiazole-5-sulfonimid- amide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 3^(rd) peak 484 318  159ba

(S, S) or (S, R) or (R, R) or (R, S)-N-((4-cyano-3- fluoro-2,6-diisopropyl- phenyl)carbamoyl)-2-(1,2- dihydroxypropan-2-yl)- thiazole-5-sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 4^(th) peak 484 319 137a

(S) or (R)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)- carbamoyl)-6-(2-hydroxy- propan-2-yl)-pyridine-3- sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 415 320 137b

(R) or (S)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)- carbamoyl)-6-(2-hydroxy- propan-2-yl)pyridine-3- sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 415 321  317ab

(S, S) or (S, R)-2-(2- hydroxypropan-2-yl)-N′- ((1-methyl-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)thiazole-5- sulfonimidamide (from Example 291) 1^(st) and 2^(nd) peak (two isomers) Faster-eluting on column 1: CHIRAL ART Cellulose-SB, 2*25 cm, 5 um, IPA in Hex (0.1% FA). Separated further on column 2: CHIRALPAK IE, EtOH in MTBE (0.1% FA) to obtain single isomers. 435 322  317aa

(S, R) or (S, S)-2-(2- hydroxypropan-2-yl)-N′- ((1-methyl-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)thiazole-5- sulfonimidamide (from Example 291) 435 323  317bb

(R, R) or (R, S)-2-(2- hydroxypropan-2-yl)-N′- ((1-methyl-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)thiazole-5- sulfonimidamide (from Example 291) CHIRAL ART Cellulose- SB, 2*25 cm, 5 um IPA in Hex (0.1% FA) 3^(nd) peak 435 324  317ba

(R, S) or (R, R)-2-(2- hydroxypropan-2-yl)-N′- ((1-methyl-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)thiazole-5- sulfonimidamide (from Example 291) IPA in Hex (0.1% FA) 4^(th) peak 435 325 316a

(S) or (R)-N′-((6-ethyl-1H- indazol-7-yl)carbamoyl)- 2-(2-hydroxypropan-2- yl)thiazole-5-sulfonimid- amide Chiralpak ID, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 409 326 316b

(R) or (S)-N′-((6-ethyl-1H- indazol-7-yl)carbamoyl)- 2-(2-hydroxy-propan-2- yl)thiazole-5-sulfonimid- amide Cliiralpak ID, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 409 327 373a

(S) or (R)-N′-((6-ethyl-1- methyl-1H-indazol-7-yl)- carbamoyl)-5-(2-hydroxy- propan-2-yl)thiazole-2- sulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um EtOH in Hex (0.1% FA) 423 328 373b

(R) or (S)-N′-((6-ethyl-1- methyl-1H-indazol-7-yl)- carbamoyl)-5-(2-hydroxy- propan-2-yl)thiazole-2- sulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um EtOH in Hex (0.1% FA) 423 329 374a

(S) or (R)-N′-((6-ethyl-2- methyl-2H-indazol-7-yl)- carbamoyl)-5-(2-hydroxy- propan-2-yl)thiazole-2- sulfonimidamide CHIRAL ART Cellulose- SB S-5 um, 250*20 mm EtOH in Hex (0.1% FA) 423 330 374b

(R) or (S)-N′-((6-ethyl-2- methyl-2H-indazol-7-yl)- carbamoyl)-5-(2-hydroxy- propan-2-yl)thiazole-2- sulfonimidamide CHIRAL ART Cellulose- SB S-5 um, 250*20 mm EtOH in Hex (0.1% FA) 423 331  319ab

(S, S) or (S, R)-2-(2- hydroxypropan-2-yl)-N′- ((3-methyl-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)thiazole-5- sulfonimidamide 1^(st) peak CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 435 332  319aa

(R, R) or (R, S)-2-(2- hydroxypropan-2-yl)-N′- ((3-methyl-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)thiazole-5- sulfonimidamide 2^(nd) peak CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 435 333  319bb

(S, R) or (S, S)-2-(2- hydroxypropan-2-yl)-N′- ((3-methyl-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)thiazole-5- sulfonimidamide 3^(rd) peak CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 435 334  319ba

(R, S) or (R, R)-2-(2- hydroxypropan-2-yl)-N′- ((3-methyl-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)thiazole-5- sulfonimidamide 4^(th) peak CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 435 335 320a

(S) or (R)-2-(2-Hydroxy- propan-2-yl)-N′-((1-oxo- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- thiazole-5-sulfonimidamide from Example 293 Chiralpak IA, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 435 336 320b

(R) or (S)-2-(2-Hydroxy- propan-2-yl)-N′-((1-oxo- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- thiazole-5-sulfonimidamide from Example 293 Chiralpak IA, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 435 337  323ab

(R, R) or (R, S)-N′-((1- hydroxy-1,2,3,5,6,7-hexa- hydro-s-indacen-4-yl)- carbamoyl)-2-(2-hydroxy- propan-2-yl)thiazole-5- sulfonimidamide (from example 336) CHIRALPAK AD, 2*25 cm, 5 um EtOH (0.1% DEA) in CO₂, 2^(nd) peak 437 338  323bb

(R, S) or (R, R)-N′-((1- hydroxy-1,2,3,5,6,7-hexa- hydro-s-indacen-4-yl)- carbamoyl)-2-(2-hydroxy- propan-2-yl)thiazole-5- sulfonimidamide (from example 336) EtOH (0.1% DEA) in CO₂, 2^(nd) peak 437 339  323aa

(S, S) or (S, R)-N′-((1- hydroxy-1,2,3,5,6,7-hexa- hydro-s-indacen-4-yl)- carbamoyl)-2-(2-hydroxy- propan-2-yl)thiazole-5- sulfonimidamide (from example 335) CHIRALPAK AD, 2*25 cm, 5 um EtOH (0.1% DEA) in CO₂, 1^(st) peak 437 340  323ba

(S, R) or (S, S)-N′-((1- hydroxy-1,2,3,5,6,7-hexa- hydro-s-indacen-4-yl)- carbamoyl)-2-(2-hydroxy- propan-2-yl)thiazole-5- sulfonimidamide (from example 335) EtOH (0.1% DEA) in CO₂, 2^(nd) peak 437 341 303a

(R) or (S)-4-(2-hydroxy- propan-2-yl)-N′-((2,4,5,6- tetrahydro-1H-cyclobuta- [f]inden-3-yl)carbamoyl)- thiazole-2-sulfonimidamide Chiralpak ID, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 407 342 303b

(R) or (S)-4-(2-hydroxy- propan-2-yl)-N′-((2,4,5,6- tetrahydro-1H-cyclobuta- [f]inden-3-yl)carbamoyl)- thiazole-2-sulfonimidamide Chiralpak ID, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 407 343 315a

(R) or (S)-2-(2-hydroxy- propan-2-yl)-N′-((3,5,6,7- tetrahydro-2H-indeno[5,6- b]furan-8-yl)carbamoyl)- thiazole-5-sulfonimidamide Chiralpak ID, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 423 344 315b

(R) or (S)-2-(2-hydroxy- propan-2-yl)-N′-((3,5,6,7- tetrahydro-2H-indeno[5,6- b]furan-8-yl)carbamoyl)- thiazole-5-sulfonimidamide Chiralpak ID, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 423 345 138a

(R) or (S)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-6-(2- hydroxypropan-2-yl)-2- methylpyridine-3-sulfon- imidamide CHIRALPAK IF, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 429 346 138b

(R) or (S)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-6-(2- hydroxypropan-2-yl)-2- methylpyridine-3-sulfon- imidamide CHIRALPAK IF, 2*25 cm, 5 um EtOH in Hex (8 mM NH3• MeOH) 429 347 328a

(R) or (S)-5-(2-hydroxy- propan-2-yl)-N′-((3,5,6,7- tetrahydro-2H-indeno[5,6- b]furan-4-yl)carbamoyl)- thiazole-2-sulfonimidamide CHIRALPAK IC, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 423 348 328b

(S) or (R)-5-(2-hydroxy- propan-2-yl)-N′-((3,5,6,7- tetrahydro-2H-indeno[5,6- b]furan-4-yl)carbamoyl)- thiazole-2-sulfonimidamide CHIRALPAK IC, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 423 349 326b

(S) or (R)-5-(2-hydroxy- propan-2-yl)-N′-((3,5,6,7- tetrahydro-2H-indeno- [5,6-b]furan-8-yl)carbam- oyl)thiazole-2-sulfonimid- amide CHIRALPAK IG, 20*250 mm, 5 um IPA in Hex: DCM = 5:1 (0.1% FA) 423 350 326a

(R) or (S)-5-(2-hydroxy- propan-2-yl)-N′-((3,5,6,7- tetrahydro-2H-indeno- [5,6-b]furan-8-yl)carbam- oyl)thiazole-2-sulfonimid- amide CHIRALPAK IG, 20*250 mm, 5 um IPA in Hex: DCM = 5:1 (0.1% FA) 423 351 318a

(S) or (R)-N′-((8-bromo- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- 5-(2-hydroxypropan-2-yl)- thiazole-2-sulfonimidamide CHIRAL ART Cellulose- SB S-5 um, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃• MeOH) 499 352 318b

(R) or (S)-N′-((8-bromo- 1,2,3,5,6,7-hexahydro-s- indacen-4-carbamoyl)-5- (2-hydroxypropan-2-yl)- thiazole-2-sulfonimidamide CHIRAL ART Cellulose- SB S-5 um, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃• MeOH) 499 353 325a

(S) or (R)-4-(2-hydroxy- propan-2-yl)-N′-((3,5,6,7- tetrahydro-2H-indeno- [5,6-b]furan-8-yl)carbam- oyl)thiazole-2-sulfonimid- amide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 423 354 325b

(R) or (S)-4-(2-hydroxy- propan-2-yl)-N′-((3,5,6,7- tetrahydro-2H-indeno- [5,6-b]furan-8-yl)carbam- oyl)thiazole-2-sulfonimid- amide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 423 355 329a

(R) or (S)-2-(2-hydroxy- propan-2-yl)-N′-(tricyclo- [6.2.0.03,6]deca-1,3(6),7- trien-2-ylcarbamoyl)- thiazole-5-sulfonimidamide Chiralpak ID, 2*25 cm, 5 um IPA in Hex (0.1% FA) 393 356 329b

(S) or (R)-2-(2-hydroxy- propan-2-yl)-N′-(tricyclo- [6.2.0.03,6]deca-1,3(6),7- trien-2-ylcarbamoyl)- thiazole-5-sulfonimidamide Chiralpak ID, 2*25 cm, 5 um IPA in Hex (0.1% FA) 393 357 404b

(R) or (S)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)- carbamoyl)-4-(2-hydroxy- propan-2-yl)-N,N-dimeth- ylthiophene-2-sulfonimid- amide CHIRALPAK IG, 20*250 mm, 5 um IPA in Hex: DCM = 3:1 (10 mM NH₃- MeOH) 448 358 404a

(S) or (R)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)- carbamoyl)-4-(2-hydroxy- propan-2-yl)-N,N-dimeth- ylthiophene-2-sulfonimid- amide CHIRALPAK IG, 20*250 mm, 5 um IPA in Hex: DCM = 3:1 (10 mM NH₃-MeOH) 448 359 332a

(R) or (S)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)- carbamoyl)-4-(2-hydroxy- propan-2-yl)-5-methyl- thiazole-2-sulfonimidamide Chiralpak ID, 2*25 cm, 5 um IPA in Hex (0.1% FA) 435 360 332b

(S) or (R)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)- carbamoyl)-4-(2-hydroxy- propan-2-yl)-5-methyl- thiazole-2-sulfonimid- amide Chiralpak ID, 2*25 cm, 5 um IPA in Hex (0.1% FA) 435 361 335a

(R) or (S)-4-(2-(dimethyl- amino)propan-2-yl)-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- benzenesulfonimidamide CHIRALPAK IG, 2.0*25 cm (5 um) IPA in Hex (8 mM NH₃- MeOH) 441 362 335b

(S) or (R)-4-(2-(dimethyl- amino)propan-2-yl)-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- benzenesulfonimidamide CHIRALPAK IG, 2.0*25 cm (5 um) IPA in Hex (8 mM NH₃- MeOH 441 363 336a

(S) or (R)-2-(2-Hydroxy- propan-2-yl)-N′-((3-oxo- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- thiazole-5-sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in MTBE (10 mM NH₃- MeOH) 435 364 336b

(R) or (S)-2-(2-Hydroxy- propan-2-yl)-N′-((3-oxo- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- thiazole-5-sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in MTBE (10 mM NH₃- MeOH) 435 365 337a

(S) or (R)-N-(4-(N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- sulfamidimidoyl)benzyl)- N-methylacetamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 441 366 337b

(R) or (S)-N-(4-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- sulfamidimidoyl)benzyl)- N-methylacetamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (8 nM NH₃- MeOH) 441 367 371a

(S) or (R)-N-(3-(N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- sulfamidimidoyl)benzyl)- N-methylacetamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 441 368 371b

(R) or (S)-N-(3-(N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- sulfamidimidoyl)benzyl)- N-methylacetamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 441 369 372a

(S, R/S) or (R, R/S)-N′- ((3-hydroxy-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)- thiazole-5-sulfonimidamide Obtained from Example 363 N/A 435 (M − 1) 370 372b

(R, R/S) or (S, R/S)-N′- ((3-hydroxy-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)- thiazole-5-sulfonimidamide Obtained from Example 364 N/A 435 (M − 1) 371 334a

(S) or (R)-4-(1-(dimethyl- amino)ethyl)-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- benzenesulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um IPA in Hex (8 mM NH₃- MeOH) 427 372 334b

(R) or (S)-4-(1-(dimethyl- amino)ethyl)-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- benzenesulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um IPA in Hex (8 mM NH₃- MeOH) 427 373 339a

(R) or (S)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)-N- methylthiazole-5-sulfon- imidamide CHIRALPAK IE, 2*25 cm, 5 um IPA in Hex (8 mM NH₃- MeOH) 435 374 339b

(S) or (R)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)-N- methylthiazole-5-sulfon- imidamide CHIRALPAK IE, 2*25 cm, 5 um IPA in Hex (8 mM NH₃- MeOH) 435 375  334ab

(S, R) or (S, S) or (R, S) or (R,R)-4-(1-(dimethyl- amino)ethyl)-N′- ((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)- benzenesulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 427 376  334aa

(S, S) or (S, R) or (R, R) or (R, S)-4-(1-(dimethyl- amino)ethyl)-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- benzenesulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 427 377  334bb

(R, R) or (R, S) or (S, S) or (S, R)-4-(1-(dimethyl- amino)ethyl)-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- benzenesulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 427 378  334ba

(R, S) or (R, R) or (S, R) or (S, S)-4-(1-(dimethyl- amino)ethyl)-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- benzenesulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 427 379 338a

(R) or (S)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-4-((3- methoxyazelidin-1-yl)- methyl)benzenesulfonimid- amide CHIRALPAK IF, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 455 380 338b

(S) or (R)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-4-((3- methoxyazetidin-1-yl)- methyl)benzenesulfonimid- CHIRALPAK IF, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 455 381 340a

(R) or (S)-5-((dimethyl- amino)methyl)-3-fluoro- N′-((1,2,3,5,6,7-hexa- hydro-s-indacen-4-yl)- carbamoyl)thiophene-2- sulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um Hex (0.1% DEA): EtOH = 50:50 437 382 340b

(S) or (R)-5-((dimethyl- amino)methyl)-3-fluoro- N′-((1,2,3,5,6,7-hexa- hydro-s-indacen-4-yl)- carbamoyl)thiophene-2- sulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um Hex (0.1% DEA): EtOH = 50:50 437 383 361b

(R) or (S)-4-((dimethyl- amino)methyl)-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- N-methylbenzenesulfon- imidamide CHIRALPAK IE, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 427 384 361a

(S) or (R)-4-((dimethyl- amino)methyl)-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- N-methylbenzenesulfon- imidamide CHIRALPAK IE, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 427 385 113a

(R) or (S)-3-fluoro-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- 5-(2-hydroxypropan-2- yl)thiophene-2-sulfonimid- amide CHIRALPAK IG, 20*250 cm, 5 um IPA in Hex (8 mM NH₃- MeOH 438 386 113b

(S) or (R)-3-fluoro-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- 5-(2-hydroxypropan-2-yl)- thiophene-2-sulfonimid- amide CHIRALPAK IG, 20*250 cm, 5 um IPA in Hex (8 mM NH₃- MeOH) 438 387 330a

(S) or (R)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-2-(2-meth- oxypropan-2-yl)thiazole- 5-sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 435 388 330b

(R) or (S)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-2-(2-meth- oxypropan-2-yl)thiazole- 5-sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 435 389 341a

(S) or (R)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-4-(((2-meth- oxyethyl)(methyl)amino)- methyl)benzenesulfonimid- amide CHIRAL Cellulose-SB 4.6*100 mm 3 um Hex (0.1% DEA): EtOH = 70:30 457 390 341b

(R) or (S)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-4-(((2-meth- oxyethyl)(methyl)amino)- methyl)benzenesulfonimid- amide CHIRAL Cellulose-SB 4.6*100 mm 3 um Hex (0.1% DEA): EtOH = 70:30 457 391  360ba

(R, R) or (R, S) or (S, S) or (S, R)-N′-((3-hydroxy- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- 2-(2-hydroxypropan-2- yl)thiazole-5-sulfonimid- amide (from Example 370) CHIRALPAK IG, 20*250 mm, 5 um EtOH in MTBE (10 mM NH₃-MeOH) 437 392  360bb

(R, S) or (R, R) or (S, R) or (S, S)-N′-((3-hydroxy- 1,2,3,5,6,7-hexahydroxy- indacen-4-yl)carbamoyl)- 2-(2-hydroxypropan-2- yl)thiazole-5-sulfonimid- amide (from Example 370) CHIRALPAK IG, 20*250 mm, 5 um EtOH in MTBE (10 mM NH₃-MeOH) 437 393 363b

(R)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl- 1,1,1,3,3,3-d₆)thiazole-5- sulfonimidamide CHIRALPAK IG, 2*25 cm, 5 um 40% MeOH in CO₂ 427 394 363a

(S)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl- 1,1,1,3,3,3-d₆)thiazole-5- sulfonimidamide CHIRALPAK IF, 2*25 cm, 5 um 40% MeOH in CO₂ 427 395 343a

(R) or (S)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-2-methyl- 1,2,3,4-tetrahydroisoquin- oline-6-sulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um EtOH in Hex (8 mM NH₃- MeOH 425 396 343b

(S) or (R)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-2-methyl- 1,2,3,4-tetrahydroisoquin- oline-6-sulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um EtOH in Hex (8 mM NH₃- MeOH 425 397 359a

(R) or (S)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-1-methyl- 1H-indazole-5-sulfonimid- amide Chiralpak ID, 2*25 cm, 5 um IPA in Hex: DCM = 3:1 (10 mM NH₃- MeOH) 410 398 359b

(S) or (R)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-1-methyl- 1H-indazole-5-sulfonimid- amide Chiralpak ID, 2*25 cm, 5 um IPA in Hex: DCM = 3:1 (10 mM NH₃- MeOH) 410 399 352a

(R) or (S)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-4-(2-meth- oxypropan-2-yl)benzene- sulfonimidamide CHIRALPAK IG, 2.0*25 cm, 5 um Hex (0.1% DEA): IPA = 70:30 428 400 352b

(S) or (R)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-4-(2-meth- oxypropan-2-yl)benzene- sulfonimidamide CHIRALPAK IG, 2.0*25 cm, 5 um Hex (0.1% DEA): IPA = 70:30 428 401 383a

(R) or (S)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-6-isopropyl- pyridine-3-sulfonimidamide CHIRALPAK IG, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 399 402 383b

(S) or (R)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-6-isopropyl- pyridine-3-sulfonimidamide CHIRALPAK IG, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 399 403 382a

(R) or (S)-2-fluoro-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- 4-((methylamino)methyl)- benzenesulfonimidamide CHIRALPAK IG, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 417 404 382b

(S) or (R)-2-fluoro-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- 4-((methylamino)methyl)- benzenesulfonimidamide CHIRALPAK IG, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃• MeOH) 417 405 379a

(R) or (S)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-4-isopropyl- thiophene-2-sulfonimid- amide CHIRALPAK IG, 2.0*25 cm, (5 um) EtOH in Hex (8 mM NH₃- MeOH) 404 406 379b

(S) or (R)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-4-isopropyl- thiophene-2-sulfonimid- amide CHIRALPAK IG, 2.0*25 cm, (5 um) EtOH in Hex (8 mM NH₃- MeOH) 404 407 380a

(R, R) or (R, S) or (S, S) or (S, R)-N-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-4-(1-meth- ylpyrrolidin-2-yl)benzene- sulfonimidamide CHIRALPAK IG, 2.0*250 mm, 5 um IPA in Hex: DCM = 5:1 (10 mM NH₃- MeOH) 439 408 380b

(S, R) or (S, S) or (R, S) or (R, R)-N-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-4-(1-methyl- pyrrolidin-2-yl)benzene- sulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um IPA in Hex: DCM = 5:1 (10 mM NH₃- MeOH) 439 409 380c

(R, S) or (S, R) or (S, R) or (R, R)-N-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-4-(1-meth- ylpyrrolidin-2-yl)benzene- sulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um IPA in Hex: DCM = 5:1 (10 mM NH₃- MeOH) 439 410 380d

(R, S) or (S, R) or (R, S or (S, S)-N-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-4-(1-meth- ylpynolidin-2-yl)benzene- sulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um IPA in Hex: DCM = 5:1 (10 mM NH₃- MeOH) 439 411 384a

(R) or (S)-4-(aminomethyl)- N′-((1,2,3,5,6,7-hexahydro- 5-indacen-4-yl)carbamoyl)- benzenesulfonimidamide CHIRALPAK IG, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 385 412 384b

(S) or (R)-4-(aminomethyl)- N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)- benzenesulfonimidamide CHIRALPAK IG, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 385 413 357a

(R) or (S)-5-((dimethyl- amino)methyl)-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- pyridine-2-sulfonimid- amide CHIRALPAK AD-H, 2.0.*25 cm EtOH in Hex (8 mM NH₃- MeOH) 414 414 357b

(S) or (R)-5-((dimethyl- amino)methyl)-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- pyridine-2-sulfonimid- amide CHIRALPAK AD-H, 2.0.*25 cm EtOH in Hex (8 mM NH₃- MeOH) 414 415 354a

(R) or (S)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-6-isobutyl- pyridine-3-sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% DEA) 413 416 354b

(S) or (R)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-6-isobutyl- pyridine-3-sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% DEA) 413 417 387a

(R) or (S)-2-acetyl-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- thiazole-5-sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um IPA in CO₂ 405 418 387b

(S) or (R)-2-acetyl-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- thiazole-5-sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um IPA in CO₂ 405 419 333a

(R) or (S)-N′-((1,2,3,6,7,8- hexahydro-as-indacen-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thia- zole-5-sulfonimidamide CHIRALPAK IF, 5*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 421 420 333b

(S) or (R)-N′-((1,2,3,6,7,8- hexahydro-as-indacen-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)- thiazole-5-sulfonimid- amide CHIRALPAK IF, 5*25 cm, 5 um EtOH in Hex (8 mM NH₃- MeOH) 421 421 375a

(R) or (S)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl- 3,3,5,5-d₄)carbamoyl)-2- (2-hydroxypropan-2-yl)- thiazole-5-sulfonimidamide CHIRALPAK IF, 2*25 cm, 5 um MeOH (2 mM NH₃- MeOH) in CO₂ 425 422 375b

(S) or (R)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl- 3,3,5,5-d₄)carbamoyl)-2- (2-hydroxypropan-2-yl)- thiazole-5-sulfonimidamide CHIRALPAK IF, 2*25 cm, 5 um MeOH (2 mM NH₃- MeOH) in CO₂ 425 423 376a

(R) or (S)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl- 1,1,7,7-d₄)carbamoyl)-2- (2-hydroxypropan-2-yl)- thiazole-5-sulfonimidamide CHIRALPAK ID, 2*25 cm, (5 um) MeOH (2 mM NH₃- MeOH) in CO₂ 425 424 376b

(S) or (R)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl- 1,1,7,7-d₄)carbamoyl)-2- (2-hydroxypropan-2-yl)- thiazole-5-sulfonimidamide CHIRALPAK ID, 2*25 cm, (5 um) MeOH (2 mM NH₃- MeOH) in CO₂ 425 ^(#)The amount of NH₃ in this chiral chromatographic solvent and similar solvents were adjusted by adding 2 M NH₃ in methanol to the desired NH₃ concentration. In this case, the resulting concentration of NH₃ in methanol is 8 mM.

Example 425 (Compound 318) 1-{Amino[5-(2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]oxo-λ⁶-sulfanylidene}-3-(8-bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea

Step 1: 4-Bromo-1,2,3,5,6,7-hexahydro-8-isocyanato-s-indacene

To a solution of 8-bromo-1,2,3,5,6,7-hexahydros-indacen-4-amine (1.5 g, 5.94 mmol) in anhydrous THF (50 mL) was added triethylamine (1.07 mL, 7.73 mmol) and triphosgene (882 mg, 2.97 mmol) at room temperature. The resulting mixture was then stirred at 60° C. for 4 h. Reaction mixture was then brought to room temperature and used directly in the next step.

Step 2: 1-{Amino[5-(2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]oxo-λ⁶-sulfanylidene}-3-(8-bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea

To a solution of N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1,3-thiazole-2-sulfonoimidamide (400 mg, 1.2 mmol) in anhydrous THF (10 mL) was added NaH (60% wt. oil dispersion, 96 mg, 2.4 mmol) at room temperature. After 5 min, a solution of 4-bromo-1,2,3,5,6,7-hexahydro-8-isocyanato-s-indacene (2 mL, 2 mmol, from Step 1) was added drop wise. The resulting mixture was stirred at room temperature for 20 min before quenching carefully with 4 M HCl solution in dioxane (3 mL). Saturated aqueous ammonium chloride was added and the mixture was extracted with dichloromethane (15 mL×3). The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated in vacuo. The crude product was purified by prep-HPLC to obtain the titled compound (280 mg, 47%). LCMS: [M+H]⁺=499.3.

Example 426 (Compound 313) 1-{Amino[5-(2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]oxo-λ⁶-sulfanylidene}-3-[7-(3,4-dimethylphenyl)-2,3-dihydro-1H-inden-4-yl]urea

Step 1: N-(2,3-dihydro-1H-inden-4-yl)acetamide

To a solution of 2,3-dihydro-1H-inden-4-amine (3.4 g, 26 mmol) in ethanol (45 mL) was added a solution of acetic anhydride (4.9 mL, 52 mmol) in ethanol (15 mL) dropwise at 0° C. The resulting mixture was gradually warmed up to RT and stirred for 15 h. Solvent was removed under reduced pressure and the residue was triturated with diethyl ether to afford titled compound as off white solid (3 g, 66%). LCMS [M+H]⁺=176.3.

Step 2: N-(4-bromo-2,3-dihydro-1H-inden-7-yl)acetamide

Into a 250-mL round-bottom flask was added N-(2,3-dihydro-1H-inden-4-yl)acetamide (3 g, 17.1 mmol) and acetic acid (45 mL). The resulting solution was cooled to 0° C. and then a solution of bromine (5.4 g, 34.2 mmol) in acetic acid (12 mL) was added dropwise with stirring over 10 min. The cooling bath was removed and the reaction mixture was stirred at RT for 1 h. Water was added and the resulting precipitates of product were collected by filtration and dried under vacuum to afford titled compound as off white solid (3.9 g, 90%). LCMS [M+H]⁺=254.4.

Step 3: N-(2,3-dihydro-4-(3,4-dimethylphenyl)-1H-inden-7-yl)acetamide

A mixture of N-(4-bromo-2,3-dihydro-1H-inden-7-yl)acetamide (1 g, 3.9 mmol), 3,4-dimethylphenylboronic acid (700 mg, 4.68 mmol), Pd(dppf)Cl₂.DCM (160 mg, 0.19 mmol), sodium carbonate (900 mg, 8.58 mmol as 2 M aqueous solution) in dioxane (12 mL) was stirred at 100° C. in an oil bath for 72 h. The reaction mixture was brought to RT, water (20 mL) was added and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using 0-30% gradient of EtOAc in hexanes to afford titled compound (880 mg, 81%). LCMS [M+H]⁺=280.6.

Step 4: 2,3-Dihydro-7-(3,4-dimethylphenyl)-1H-inden-4-amine

A solution of N-(2,3-dihydro-4-(3,4-dimethylphenyl)-1H-inden-7-yl)acetamide (880 mg, 3.15 mmol) in 6 N HCl (20 mL) was stirred at 100° C. for 40 h. After consumption of the starting material, the reaction mixture was cooled to 0° C. and adjusted to pH=8 with 10 M aqueous sodium hydroxide solution. The precipitates formed were collected, washed with water and dried under vacuum to afford the titled compound (81 mg, 67%) as tan colored powder. LCMS [M+H]⁺=238.3.

Step 5: 1-{Amino[5-(2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]oxo-λ⁶-sulfanylidene}-3-[7-(3,4-dimethylphenyl)-2,3-dihydro-1H-inden-4-yl]urea

To a solution of N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1,3-thiazole-2-sulfonoimidamide (42 mg, 0.13 mmol) in DMF (1 mL) was added Et₃N (35 uL, 0.25 mmol) and the resulting mixture was stirred at room temperature for 10 min, followed by the addition of CDI (41 mg, 0.25 mmol). The reaction mixture was further stirred at RT for 1 h, and then 2,3-dihydro-7-(3,4-dimethylphenyl)-1H-inden-4-amine (30 mg, 0.13 mmol) was added. The resulting reaction mixture was stirred overnight at room temperature. The presence of desired product was then confirmed by LC-MS. The reaction mixture was quenched with 4 M HCl in dioxane (1 mL) and stirred for 30 min to de-protect the TBS group which indicated the formation of desired product on LCMS. The crude product was purified by preparative HPLC to provide titled compound (16.4 mg, 27%). LCMS [M+H]⁺=485.49.

Example 427 (Compound 314) 1-{Amino[5-(2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]oxo-λ⁶-sulfanylidene}-3-[8-(3,4-dimethylphenyl)-1,2,3,5,6,7-hexahydro-s-indacen-4-yl]urea

Step 1: 1,2,3,5,6,7-Hexahydro-8-(3,4-dimethylphenyl)-s-indacen-4-amine

8-Bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (105 mg, 0.42 mmol), 3,4-dimethylphenyl-boronic acid (187 mg, 1.25 mmol), Pd(dppf)Cl₂ (30.4 mg, 0.04 mmol) and dioxane (1.5 mL) were added to a reaction vial. Cesium carbonate (1.24 mL, 1 M in H₂O) was then added and the reaction mixture was stirred at 80° C. for 16 h. Reaction mixture was brought to RT and filtered through a small bed of Celite and rinsed with dioxane (5 mL). Water (5 mL) was added to the filtrates and extracted with diethyl ether (5 mL×3). The combined organic layers were washed with brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo to provide titled compound which was used in the next step without any purification. LCMS [M+H]⁺=278.4.

Step 2: 1-{Amino[5-(2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]oxo-λ⁶-sulfanylidene}-3-[8-(3,4-dimethylphenyl)-1,2,3,5,6,7-hexahydro-s-indacen-4-yl]urea

The title product was obtained using similar procedure as in Step 5 Example 426. LCMS: [M+H]⁺=525.42.

Example 428 (Compound 309) 3-[Amino(dimethyl-1,3-thiazol-5-yl)oxo-λ⁶-sulfanylidene]-1-[4-fluoro-2,6-bis(propan-2-yl)phenyl]urea

Step 1: N-(tert-butyldimethylsilyl)-2,4-dimethyl-1,3-thiazole-5-sulfonamide

Dimethyl-1,3-thiazole-5-sulfonamide (41.4 mg, 0.22 mmol) was dissolved in anhydrous CH₂Cl₂ (2 mL). Triethylamine (0.090 mL, 0.65 mmol) and TBSCl (38 mg, 0.25 mol) were added and the resulting mixture was stirred at 50° C. for 18 h. Reaction mixture was brought to RT and used directly in the next step. LCMS: [M+H]⁺=307.2.

Step 2: N-(tert-butyldimethylsilyl)-2,4-dimethyl-1,3-thiazole-5-sulfonoimidamide

Polymer bound dichlorotriphenylphosphorane reaction mixture (described for Reagent 2) was cooled in an ice/water bath under nitrogen. Triethylamine (0.1 mL, 0.72 mmol, 2.25 equiv.) was added slowly via syringe. Resulting mixture was stirred at 0° C. for 10 min and then the reaction mixture from Step 1 above was added dropwise via syringe. This reaction mixture was further stirred at 0° C. for 30 min and then a steady stream of anhydrous ammonia was bubbled into the reaction mixture for 3 min. Reaction vial was screw capped and stirred in ice/water bath for 2 h. Reaction mixture was warmed up to room temperature, carefully opened and filtered to remove resin. The cloudy filtrate was centrifuged to remove any solids. Supernatant was concentrated in vacuo and dried under high vacuum for 1 h and used directly in the next step. LCMS: [M+H]⁺=306.8.

Step 3: 3-{[(Tert-butyldimethylsilyl)amino](dimethyl-1,3-thiazol-5-yl)oxo-λ⁶-sulfanylidene}-1-[4-fluoro-2,6-bis(propan-2-yl)phenyl]urea

To the crude reaction mixture from Step 2 was added anhydrous THF (1.5 mL) and the resulting mixture was stirred in an ice/water bath for 5 min. NaH (17 mg, 0.44 mmol) was added and after 2 min of stirring a solution of isocyanate (0.165 mmol) in THF (3 ml) was added dropwise at 0° C. The resulting mixture was brought to RT and stirred for 15 min to give a mixture of crude products. LCMS: [M+H]⁺=527.5; for de-protected product, [M+H]⁺=413.5.

Step 4: 3-[amino(dimethyl-1,3-thiazol-5-yl)oxo-λ⁶-sulfanylidene]-1-[4-fluoro-2,6-bis(propan-2-yl)phenyl]urea

To the reaction from Step 3 was carefully added 4N HCl in dioxane (0.3 mL) and the resulting mixture was stirred at RT for 30 min or till the completion of reaction as determined by the LCMS analysis ([M+H]⁺=413.5). Reaction mix was then concentrated in vacuo. DMSO (0.8 mL) was added to the residue and purified by prep-HPLC to afford titled compound (10 mg).

Examples in the following table were prepared using similar procedures described in Example 428.

TABLE 29 Final LCMS: Example # Target # IUPAC Name Structure [M + H]⁺ 428 309 3-[amino(dimethyl-1,3-thiazol- 5-yl)oxo-λ6-sulfanylidene]-1-[4- fluoro-2,6-bis(propan- 2-yl)phenyl]urea

413.16 430 310 3-[amino({1-methyl-1H- pyrazolo[3,4-b]pyridin-5- yl})oxo-λ⁶-sulfanylidene]-1[4- fluoro-2,6-bis(propan-2- yl)phenyl]urea

433.27 431 306 1-{amino[5- (dimethylamino)naphthalen-1- yl]oxo-λ⁶-sulfanylidene}-1-3-[4- fluoro-2,6-bis(propan-2- yl)phenyl]urea

471.70

Example 281 (Compound 378)

3-Fluoro-5-(2-hydroxypropan-2-yl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)thiophene-2-sulfonimidamide (Scheme 1) Examples 432 (Compound 378a) and Example 433 (Compound 378b)

(R)- and (S)-3-Fluoro-5-(2-hydroxypropan-2-yl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)-carbamoyl)thiophene-2-sulfonimidamide

Step 1: N-(tert-butyldimethylsilyl)-3-fluoro-5-(2-hydroxypropan-2-yl)-N′-(2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-ylcarbamoyl)thiophene-2-sulfonimidamide

To a stirred solution of N′-(tert-butyldimethylsilyl)-3-fluoro-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide (200 mg, 0.57 mmol) in THF (15 mL) in a 100 mL 3-necked round-bottom flask under nitrogen was added NaH (60% oil dispersion, 68 mg, 1.70 mmol) in one portion at 0° C., then 3-isocyanato-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (105 mg, 0.57 mmol) in THF (2.0 mL) was added dropwise at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×50 mL of EtOAc and the organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by Prep-TLC (PE/EtOAc=1:1). This resulted in 110 mg (36.1%) of the title compound as a yellow solid. MS-ESI: 538 (M+1).

Step 2: 3-Fluoro-5-(2-hydroxypropan-2-yl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl) carbamoyl)thiophene-2-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-3-fluoro-5-(2-hydroxypropan-2-yl)-N′-(2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-ylcarbamoyl)thiophene-2-sulfonimidamide (100 mg, 0.19 mmol) in THF (15 mL) in a 50-mL round-bottom flask was added TBAF (146 mg, 0.56 mmol) in one portion at RT. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (3:2). The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep C18 OBD Column, 19*150 mm*5 um; mobile phase, Water (10 mM NH₄HCO₃+0.1% NH₃.H₂O) and MeCN (25% to 41% Phase B over 7 min); Detector, UV 254/210 nm. This resulted in 60 mg (76.1%) of Example 281 as a white solid. MS-ESI: 424 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.31 (s, 1H), 7.69 (br s, 2H), 6.95 (s, 1H), 6.66 (s, 1H), 5.86 (s, 1H), 3.05-2.93 (m, 2H), 2.93-2.85 (m, 2H), 2.83-2.63 (m, 4H), 2.00-1.80 (m, 2H), 1.47 (s, 3H), 1.46 (s, 3H).

Step 3: Chiral Separation

3-Fluoro-5-(2-hydroxypropan-2-yl)-N′-(2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-ylcarbamoyl)thiophene-2-sulfonimidamide (60 mg) was resolved by Chiral HPLC with the following conditions: Column: CHIRALPAK IG, 20*250 mm, 5 um; Mobile Phase A: Hex (8 mM NH₃.MeOH), Mobile Phase B: IPA; Flow rate: 20 mL/min; Gradient: 30 B to 30 B in 13 min; 220/254 nm; Rt1: 6.2 min (Example 432); Rt2: 9.46 min (Example 433). This resulted in 15 mg of Example 432 and 16 mg of Example 433, both as white solids.

Example 432 MS-ESI: 424 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (s, 1H), 7.79 (br s, 2H), 6.97 (s, 1H), 6.67 (s, 1H), 5.88 (s, 1H), 3.05-2.93 (m, 2H), 2.93-2.85 (m, 2H), 2.83-2.63 (m, 4H), 2.00-1.80 (m, 2H), 1.48 (s, 3H), 1.47 (s, 3H). Example 433 MS-ESI: 424 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (s, 1H), 7.80 (s, 2H), 6.97 (s, 1H), 6.67 (s, 1H), 5.86 (s, 1H), 3.05-2.93 (m, 2H), 2.93-2.85 (m, 2H), 2.85-2.65 (m, 4H), 2.00-1.80 (m, 2H), 1.48 (s, 3H), 1.47 (s, 3H).

TABLE 37 Examples in the following table were prepared using similar conditions as described in Example 281 and Scheme 1 from appropriate starting materials. Exact Mass Ex. # Cmpd # Structure IUPAC Name [M + H]⁺ 434 858

4-(2-Hydroxypropan-2-yl)-N′-((1-oxo-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)thiophene-2- sulfonimidamide 434 435 837

2-(2-hydroxypropan-2-yl)-N′-((1-oxo-1,2,3,6,7,8- hexahydro-as-indacen-4-yl)carbamoyl)thiazole-5- sulfonimidamide 435 436 829

2-(1,2-Dihydroxypropan-2-yl)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)thiazole-5- sulfonimidamide 437 437 842

N′-((8-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-2-(1,2-dihydroxypropan- 2-yl)thiazole-5-sulfomidamide 462 438 859

3-Fluoro-5-(2-hydroxypropan-2-yl)-N′-((1-oxo- 1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)thiophene-2-sulfonimidamide 452 439 873

N-(amino(6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazin-3- yl)(oxo)-λ⁶-sulfaneylidene)-1,2,3,5,6,7-hexahydro-s- indacene-4-carboxamide 387 440 834

N-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-2- (2-hydroxypropan-2-yl)thiazole-4-sulfonimidamide 421 441 869c

(6R)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-6-hydroxy-6,7- dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-3-sulfonimidamide 418 442 817

N′-((8-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-5-(hydroxymethyl)-1-isopropyl-1H- pyrazole-3-sulfonimidamide 443 443 411

N′-((8-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-5-(1,2-dihydroxypropan-2-yl)-3- fluorothiophene-2-sulfonimidamide 479

Example 444 (Compound 802)

4-(Azetidin-2-yl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide

Step 1: Tert-butyl 2-(4-(N-(tert-butyldimethylsilyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamidimidoyl)phenyl)azetidine-1-carboxylate

To a stirred solution of tert-butyl 2-(4-(N-(tert-butyldimethylsilyl)sulfamidimidoyl)phenyl)azetidine-1-carboxylate (80 mg, 0.19 mmol) in THF (5 mL) in a 100 mL 3 necked round-bottom flask under nitrogen was added NaH (60% oil dispersion, 15.2 mg, 0.38 mmol) in one portion at 0° C., 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (39.3 mg, 0.19 mmol) in THF (2 mL) was added dropwise at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3×50 mL of EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1/1). This resulted in 90 mg (76.6%) of the title compound as a yellow solid. MS-ESI: 625 (M+1)

Step 2: 4-(Azetidin-2-yl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoylbenzenesulfonimidamide

To a stirred solution of tert-butyl 2-(4-(N-(tert-butyldimethylsilyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)phenyl)azetidine-1-carboxylate (90 mg, 0.14 mmol) in DCM (10 mL) in a 25-mL round-bottom flask was added TFA (2 mL) dropwise at 0° C. The resulting solution was stirred for 10 min at 0° C. The resulting mixture was concentrated under reduced pressure below 30° C. The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep OBD C18 Column, 30*150 mm 5 um; mobile phase, water (10 mM NH₄HCO₃+0.1% NH₃.H₂O) and MeCN (20% to 40% Phase B over 7 min); Detector, UV 254/220 nm. This resulted in 6.10 mg (10.3%) of Example 444 as a white solid. MS-ESI: 411 (M+1).

Example 445 (Compound 870a)

(6R)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][3]oxazine-3-sulfonimidamide (Scheme II)

Step 1: Tert-butyl (R)-3-(N-(tert-butyldimethylsilyl)-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)sulfamimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl(methyl)carbamate

To a stirred solution of tert-butyl (R)-3-(N′-(tert-butyldimethylsilyl)sulfamimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl-(methyl)carbamate (1.10 g, 3.31 mmol) in THF (50 mL) in a 100-mL 3 necked round-bottom flask under nitrogen was added NaH (60% oil dispersion, 397 mg, 9.93 mmol) in portions at 0° C. The resulting solution was stirred for 20 min at RT. To this was added 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (1.32 g, 6.62 mmol) in THF (5 mL) dropwise at 0° C. The resulting solution was allowed to react, with stirring, for an additional 16 h at RT. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3×30 mL of EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (2:3). This resulted in 556 mg (35%) of the title compound as an off-white solid. MS-ESI: 645 (M+1).

Step 2: (6R)-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide

To a stirred solution of tert-butyl (R)-3-(N-(tert-butyldimethylsilyl)-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)sulfamimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl(methyl)carbamate (280 mg, 0.43 mmol) in DCM (10 mL) in a 50-mL round-bottom flask was added BF₃.Et₂O (47% wt., 289 mg, 2.0 mmol) dropwise at 0° C. The resulting solution was stirred for 2 h at 0° C. The reaction was then quenched by the addition of 0.5 mL of sat. NaHCO₃ (aq). The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep OBD C18 Column, 30*150 mm, 5 um; mobile phase, water (10 mM NH₄HCO₃+0.1% NH₃.H₂O) and MeCN (10% to 33% Phase B over 7 min); Detector, UV (254/220 nm). This resulted in 80 mg (40.9%) of Example 445 as an off-white solid. MS-ESI: 431 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.18 (br s, 1H), 7.52 (s, 1H), 7.25 (br s, 2H), 6.86 (s, 1H), 4.40-4.32 (m, 1H), 4.32-4.19 (m, 2H), 4.00-3.90 (m, 1H), 3.25-3.10 (m, 1H), 2.78 (t, J=7.4 Hz, 4H), 2.75-2.60 (m, 4H), 2.35 (d, J=2.2 Hz, 3H), 2.00-1.88 (m, 4H).

Example 446 (Compound 846)

4-((Dimethylamino)methyl)-N′-(2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-ylcarbamoyl)benzenesulfonimidamide (Scheme 3)

Step 1: Tert-butyl 4-((dimethylamino)methyl)-N-(2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-ylcarbamoyl)phenylsulfonimidoylcarbamate

To a stirred solution of tert-butyl (amino(4-((dimethylamino)methyl)phenyl)(oxo)-λ⁶-sulfaneylidene)carbamate (100 mg, 0.32 mmol) in THF (5.0 mL) a 100 mL 3 necked round-bottom flask under nitrogen was added NaH (60% oil dispersion, 25.6 mg, 0.64 mmol) in one portion at 0° C., then 3-isocyanato-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (60 mg, 0.32 mmol) in THF (5 mL) was added dropwise at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×100 mL of EtOAc and the organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. This resulted in 60 mg (37.7%) of the title compound as yellow oil. MS-ESI: 499 (M+1).

Step 2: 4-((Dimethylamino)methyl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl) benzenesulfonimidamide

To a stirred solution of tert-butyl 4-((dimethylamino)methyl)-N-(2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-ylcarbamoyl)phenylsulfonimidoylcarbamate (60 mg, 0.12 mmol) in THF (5 mL) in a 50-mL round-bottom flask was added HCl in 1,4-dioxane (4 M, 2.0 mL) dropwise at 0° C. The resulting solution was stirred for 30 min at RT. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: XBridge Shield RP18 OBD Column, 19*250 mm, 10 um; Mobile Phase A: water (10 mM NH₄HCO₃), Mobile Phase B: MeCN; Flow rate: 25 mL/min; Gradient: 46% B to 47% B in 7 min; UV 210/254 nm. This resulted in 22.8 mg (45.1%) of Example 446 as a white solid. MS-ESI: 399 (M+1). ¹H NMR (400 MHz, MeOH-d₄) δ 7.98 (d, J=8.3 Hz, 2H), 7.53 (d, J=8.3 Hz, 2H), 6.65 (s, 1H), 3.61 (s, 2H), 3.01 (s, 2H), 2.92 (s, 2H), 2.84 (t, J=7.4 Hz, 2H), 2.75 (t, J=7.3 Hz, 2H), 2.29 (s, 6H), 2.06-1.90 (m, 2H).

TABLE 38 Examples in the following table were prepared using similar conditions as described in Example 446 and Scheme 3 from appropriate starting materials. Exact Mass Ex. # Cmpd # Structure IUPAC Name [M + H]⁺ 447 847

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)- 4-(pyrrolidin-2-yl)benzenesulfonimidamide 425 448 814

4-((Methylamino)methyl)-N′-((2,4,5,6-tetrahydro- 1H-cyclobuta[f]inden-3- yl)carbamoyl)benzenesulfonimidamide 385 449 845

4-((Dimethylamino)methyl)-N′- (tricyclo[6.2.0.03,6]deca-1,3(6),7-trien-2- ylcarbamoyl)benzenesulfonimidamide 385 450 857

N′-((8-chloro-1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide 455/457

Example 451 (Compound 853)

2-Fluoro-N′-(1,2,3,5,6,7-hexahydros-indacen-4-ylcarbamoyl)-4-(2-(methylamino)propan-2-yl)benzenesulfonimidamideonimidamide (Scheme III)

Step 1: Tert-butyl 2-(4-(N-(tert-butyldiphenylsilyl)-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl) sulfamimidoyl)-3-fluorophenyl)propan-2-yl(methyl)carbamate

To a stirred solution of tert-butyl 2-(4-(N-(tert-butyldiphenylsilyl)sulfamimidoyl)-3-fluorophenyl)propan-2-yl(methyl) carbamate (400 mg, 0.69 mmol) in THF (10 mL) in a 100-mL round-bottom flask under nitrogen was added NaH (60% oil dispersion, 82.2 mg, 2.06 mmol) in portions at 0° C., then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (136 mg, 0.685 mmol) in THF (5 mL) was added dropwise at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×30 mL of EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. This resulted in 400 mg (74.6%) of the title compound as a yellow solid. MS-ESI: 783 (M+1).

Step 2: 2-Fluoro-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)-4-(2-(methylamino)propan-2-yl) benzenesulfonimidamide

To a stirred solution of tert-butyl 2-(4-(N-(tert-butyldiphenylsilyl)-N′-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyl)sulfamimidoyl)-3-fluorophenyl)propan-2-yl(methyl)carbamate (80 mg, 0.1 mmol) in dioxane (5 mL) a 25-mL round-bottom flask under nitrogen was added cc. HCl (0.09 mL, 1.02 mmol) dropwise at 0° C. The resulting solution was stirred for 30 min at RT. The pH value of the solution was adjusted to 7 with sat. NaHCO₃ solution. The resulting solution was extracted with 3×20 mL of EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep C18 OBD Column, 198*150 mm, 5 um; mobile phase, water (10 mM NH₄HCO₃+0.1% NH₃.H₂O) and MeCN (28% to 49% Phase B over 7 min); Detector, UV 254 nm. This resulted in 11.8 mg (25.9%) of Example 451 as a white solid. MS-ESI: 445 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (br s, 1H), 7.76 (dd, J=8.0, 8.0 Hz, 1H), 7.55 (br s, 2H), 7.43 (dd, J=12.5, 1.6 Hz, 1H), 7.39 (dd, J=8.3, 1.8 Hz, 1H), 6.85 (s, 1H), 2.75 (t, J=7.4 Hz, 4H), 2.62 (t, J=7.6 Hz, 4H), 1.99 (s, 3H), 1.95-1.80 (m, 4H), 1.34 (s, 3H), 1.33 (s, 3H).

TABLE 39 Examples in the following table were prepared using similar conditions as described in Example 451 and Scheme III from appropriate starting materials. Exact Mass Ex. # Cmpd # Structure IUPAC Name [M + H]⁺ 452 826

4-(1-(Difluoromethoxy)ethyl)-N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)benzenesulfonimidamide 450

Example 453 (Compound 840)

5-(2-Hydroxypropan-2-yl)-N′-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiazole-2-sulfonimidamide (Scheme IV)

Step 1: N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-N′-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiazole-2-sulfonimidamide

To a stirred solution of N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide (1.40 g, 4.17 mmol) in THF (20 mL) in a 100 mL 3 necked round-bottom flask under nitrogen was added NaH (60% oil dispersion, 333 mg, 8.34 mmol) in portions at 0° C., then 2,2,2-trichloroethyl (3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamate (1.82 g, 5.01 mmol) in THF (10 mL) was added dropwise at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of Na₂SO₄.10H₂O (1.6 g, 5.0 mmol). The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 3.0 g (crude) of the title compound as a light yellow crude oil. MS-ESI: 549 (M+1)

Step 2: 5-(2-Hydroxypropan-2-yl)-N′-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) thiazole-2-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-N′-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiazole-2-sulfonimidamide (1.40 g, 2.55 mmol, crude) in DCM (10 mL) in a 100-mL round-bottom flask was added HF-Pyridine (70% wt., 73 mg, 2.55 mmol). The resulting solution was stirred for 16 h at RT. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep OBD C18 Column, 30*150 mm, 5 um; mobile phase, water (10 mM NH₄HCO₃) and MeCN (22% to 24% Phase B over 7 min); Detector, UV 220 nm. This resulted in 540 mg (28.8% over 2 steps) of Example 453 as a white solid. MS-ESI: 435 (M+1). ¹H NMR (400 MHz, MeOH-d₄) δ 7.78 (s, 1H), 7.13 (s, 1H), 3.07-3.04 (m, 2H), 2.91 (t, J=7.3 Hz, 2H), 2.82-2.78 (m, 2H), 2.70-2.68 (m, 2H), 2.04-2.01 (m, 2H), 1.66 (s, 6H).

TABLE 40 Examples in the following table were prepared using similar conditions as described in Example 453 and Scheme IV from appropriate starting materials. Exact Mass Ex. # Cmpd # Structure IUPAC Name [M + H]⁺ 454 805

N′-((8-cyano-1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)- 2-(2-hydroxypropan-2-yl)-4- (methoxymethyl)thiazole-5- sulfonimidamide 490 455 851

5-(2-Hydroxypropan-2-yl)-N′- ((1-oxo-1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)thiazole-2- sulfonimidamide 435 456 818

N′-((8-cyano-1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- 4-(2-hydroxypropan-2-yl)pyridine-2- sulfonimidamide 440 457 816

N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-5-(2- hydroxypropan-2-yl)-1-(4- methoxybenzyl)-1H-pyrazole-3- sulfonimidamide 524

Example 458 (Compound 828)

N′-((8-allyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonimidamide (Scheme 2)

Step 1: N′-((8-allyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonimidamide

To a stirred solution of N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonimidamide (82.4 mg, 0.21 mmol) in THF (5.0 mL) in a 100 mL 3 necked round-bottom flask under nitrogen was added NaH (60% oil dispersion, 25.0 mg, 0.63 mmol) in one portion at 0° C. The resulting solution was stirred for 30 min at 0° C. To the above mixture was added 4-allyl-8-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (50.0 mg, 0.21 mmol) at 0° C. The resulting mixture was stirred for additional 4 h at RT under nitrogen atmosphere. The reaction was quenched with 5 mL of water at 0° C. The resulting mixture was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (2×15 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 112 mg (85%) crude title compound as a yellow solid. MS-ESI: 634 (M+1).

Step 2: N′-((8-allyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonimidamide

To a stirred solution of N′-((8-allyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N-(tert-butyl-dimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonimidamide (110 mg, 0.17 mmol) in THF (5 mL) in a 50-mL round-bottom flask was added HF/Py (70% wt., 25 mg, 0.87 mmol) at 0° C. The resulting solution was stirred for 1 h at 25° C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Sunfire prep C18 column 30*150, 5 um; Mobile Phase A: water (0.1% FA), Mobile Phase B: MeCN; Flow rate: 60 mL/min; Gradient: 53% B to 55% B in 10 min; 254/210 nm; Rt: 7.73 min; Detector, 254/210 um. This resulted in 31.7 mg (35.0%) of Example 458 as a white solid. MS-ESI: 520 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.31 (s, 1H), 7.53 (s, 7H), 6.72 (s, IH), 5.90-5.65 (m, 1H), 5.46 (s, 1H), 4.98-4.88 (m, 2H), 3.23 (dt, J=6.5, 1.7 Hz, 2H), 2.80-2.72 (m, 4H), 2.72-2.62 (m, 4H), 1.98-1.85 (m, 4H), 1.35 (s, 3H), 1.34 (s, 3H).

TABLE 41 Example 459 was obtained during the Pre-HPLC purification from isomerizaton of Example 458 Exact Mass Ex. # Cmpd # Structure IUPAC Name [M + H]⁺ 459 843

(E)-5-(2-hydroxypropan-2-yl)- 1-phenyl-N′-((8-(prop-1-en-1- yl)-1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide 520

TABLE 42 Examples in the following table were prepared using similar conditions as described in Example 458 and Scheme 2 from appropriate starting materials. Exact Cmpd Mass Ex. # # Structure IUPAC Name [M + H]⁺ 460 801

N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-2- (1,2,3-trihydroxypropan-2-yl) thiazole-5-sulfonimidamide 453 461 806

N′-((8-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-5-(2- hydroxypropan-2-yl)pyridine-3- sulfomidamide 440 462 807

4-(azetidin-1-ylmethyl)-2-fluoro-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)benzenesulfonimidamide 443 463 808

4-(azetidin-1-ylmethyl)-2- fluoro-N′-((2,4,5,6-tetrahydro- 1H-cyclobuta[f]inden-3- yl)carbamoyl)benzenesulfonimidamide 429 464 852

N′-((1,2,3,6,7,8-hexahydro-as- indacen-4-yl)carbamoyl)-6- (2-hydroxypropan-2-yl)pyridine-3- sulfonimidamide 415 465 803

N′-((6-cyclopropyl-5-methyl- 2,3-dihydro-1H-inden-4- yl)carbamoyl)-4-(2-hydroxypropan- 2-yl)thiophene-2- sulfonimidamide 434 466 811

4-(2-Hydroxypropan-2-yl)- N′-((3-oxo-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)thiophene-2- sulfonimidamide 434 467 835

4-(2-Hydroxypropan-2-yl)- N′-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3-yl)carbamoyl)thiophene-2- sulfonimidamide 406 468 836

N′-((6-((6-5-methyl-2,3-dihydro-1H-inden-4- yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide 435 469 804

6-(2-Hydroxypropan-2-yl)-N′-((3-oxo-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)pyridine-3- sulfonimidamide 429 470 822

N′-((8-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-6-(2- hydroxypropan-2-yl)pyridine-3- sulfonimidamide 440 471 871d

N-(amino((R)-6-methoxy-6,7- dihydro-5H-pyrazolo[5,1- b][1,3]oxazin-3-yl)(oxo)-λ6- sulfaneylidene)-2,4,5,6- tetrahydro-1H-cyclobuta[f]indene- 3-carboxamide 403 472 872a

N-(amino((R)-6-methoxy-6,7- dihydro-5H-pyrazolo[5,1- b][1,3]oxazin-3-yl)(oxo)-9,6- sulfaneylidene)-1,2,3,5,6,7- hexahydro-s-indacene-4-carboxamide 416 473 815

N-(amino(3-fluoro-5-(2- hydroxypropan-2-yl)thiophen- 2-yl)(oxo)-λ⁶-sulfaneylidene)- 1,2,3,5,6,7-hexahydro-s- indacene-4-carboxamide 423 474 819

4-(1-(Dimethylamino)-2,2- difluoroethyl)-N-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)benzenesulfonimidamide 463 475 820

N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-4- (hydroxymethyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamide 451 476 501

N-(amino(6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazin-3- yl)(oxo)-λ⁶-sulfaneylidene)- 2,4,5,6-tetrahydro-1H- cyclobuta[f]indene-3-carboxamide 373 477 821

N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-4- (2-hydroxypropan-2-yl)-5-phenylthiophene-2- sulfomidamide 496 478 833

5-Fluoro-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-2-isopropylpyridine- 4-sulfonimidamide 417 479 413

N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-6- methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2- sulfonimidamide 431 480 831

4-(1-(Dimethylamino)-2-fluoroethyl)- N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)benzenesulfonimidamide 445 481 412

3-Fluoro-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-5-((methylamino) methyl)thiophene-2- sulfonimidamide 423 482 849

3-Cyano-N′-((8-cyano-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-5-(2-hydroxypropan-2- yl)benzenesulfonimidamide 464 483 850

6-Cyclopentyl-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)pyridine-3-sulfonimidamide 424 484 854

4-(Cyclopropyl(dimethylamino)methyl)-N′- ((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)benzenesulfonimidamide 453 485 855

6-(Difluoromethyl)-N′-((1,2,3,5,6,7- hexahydro-s-indacen- 4-yl)carbamoyl)pyridine-3-sulfonimidamide 407 486 860

N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-4- (2-(methylamino)propan-2-yl) benzenesulfonimidamide 427 487 861

N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-4- ((methyl(2,2,2- trifluoroethyl)amino)methyl) benzenesulfonimidamide 481 488 862

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)benzenesulfonimidamide 356 489 863

N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-4- (isopropyl(methyl)ammo) benzenesulfonimidamide 427 490 844

N′-((8-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-5-(2-hydroxypropan- 2-yl)-1-phenyl-1H- pyrazole-3-sulfonamide 505 491

N′-((8-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-4-(2-hydroxypropan-2-yl)pyridine-2- sulfonimidamide 440 492 856

4-(1-(Dimethylamino)-2,2,2-trifluoroethyl)-N′- ((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)benzenesulfonimidamide 481 493 841

4-(Difluoromethoxy)-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl) benzenesulfonimidamide 422 494 812

2-(2-Hydroxypropan-2-yl)-N′- ((6-isopropyl-2,3-dihydro- 1H-inden-5-yl)earbamoyl)thiazole-5- sulfonimidamide 423

Example 495 (Compound 810)

2-Fluoro-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(1-((methylamino)methyl)cyclopropyl)benzenesulfonimidamide (Scheme V)

Step 1: 1-(4-(N-(tert-butyldimethylsilyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) sulfamidimidoyl)-3-fluorophenyl)-N-methylcyclopropane-1-carboxamide

To a stirred solution of 1-(4-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)-3-fluorophenyl)-N-methylcyclopropane-1-carboxamide (100 mg, 0.26 mmol) in THF (5 mL) in a 25-mL round-bottom flask was added DBU (12.5 mg, 0.52 mmol) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (51.7 mg, 0.26 mmol). The resulting solution was stirred for 16 h at RT. The resulting mixture was used in the next step directly without further purification. MS-ESI: 585 (M+1).

Step 2: 1-(3-Fluoro-4-(N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)phenyl)-N-methylcyclopropane-1-carboxamide

To the solution from the step 1 was added HF-Pyridine (70% wt., 37 mg, 1.3 mmol). The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3×15 mL of EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was eluted from silica gel with PE/EtOAc (1:3). This resulted in 73.3 mg (62.1% over 2 steps) of the title compound as a yellow solid. MS-ESI: 471 (M+1).

Step 3: 2-Fluoro-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(1-((methylamino)methyl) cyclopropyl)benzenesulfonimidamide

To a stirred solution of 1-(3-fluoro-4-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-sulfamidimidoyl)phenyl)-N-methylcyclopropane-1-carboxamide (47.1 mg, 0.10 mmol) in THF (2 mL) in a 8-mL sealed tube purged with and maintained under nitrogen was added BH₃-THF (1 M, 0.5 mL, 0.50 mmol) dropwise at 0° C. The resulting solution was stirred for 16 h at 30° C. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×15 mL of EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Sunfire prep C18 column 30*150, 5 um; mobile phase, H₂O/MeCN=90:10 increasing to H₂O/MeCN=10:90 within 30 min; Detector, 254 nm. This resulted in 18.3 mg (40.0%) of Example 495 as a solid. MS-ESI: 457 (M+1).

TABLE 43 Examples in the following table were prepared using similar conditions as described in Example 495 and Scheme V from appropriate starting materials. Exact Mass Ex. # Cmpd # Structure IUPAC Name [M + H]⁺ 496 813

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2- methyl-1-(methylamino)propan-2-yl)benzenesulfonimidamide 441

Example 497 (Compound 809)

5-((Dimethylamino)methyl)-3-fluoro-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)pyridine-2-sulfonimidamide (Scheme VI)

Step 1-2 used similar procedures as step 1-2 shown in Example 495 to afford Example 497. MS-ESI: 432 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.78 (s, 1H), 8.53 (br s, 1H), 8.34 (dd, J=10.4, 1.2 Hz, 1H), 7.78 (s, 2H), 6.86 (s, 1H), 4.62 (s, 2H), 2.81 (s, 6H), 2.81-2.70 (m, 4H), 2.70-2.50 (m, 4H), 2.00-1.80 (m, 4H)

Example 499 (Compound 909)

N′-((8-Cyano-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide (Scheme VIII)

Step 1: 4-(2-Hydroxypropan-2-yl)thiazole-2-sulfonimidamide

To a stirred solution of N′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide (485 mg, 1.44 mmol) in THF (10 mL) in a 25-mL round-bottom flask was added HF/Py (70% wt., 206 mg, 7.2 mmol). The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 299 mg (93.8%) of the title compound as a yellow solid. MS-ESI: 222 (M+1).

Step 2: N′-((8-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl) thiazole-2-sulfonimidamide

To a stirred solution of 4-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide (221 mg, 1.00 mmol) in THF (20 mL) in a 50-mL round-bottom flask under nitrogen was added NaH (60% dispersion in mineral oil, 120 mg, 3.00 mmol) in one portion at 0° C., 2,2,2-trichloroethyl (8-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamate (374 mg, 1.00 mmol) was added to the solution in portions at 0° C. The resulting solution was stirred for 60 min at RT. The resulting mixture was quenched with 5 mL of water then concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: XBridge Shield RP18 OBD Column, 19*250 mm, 10 um; mobile phase, water (10 mM NH₄HCO₃) and MeCN (13% to 34% Phase B over 7 min); Detector, 254/220 nm. This resulted in 134 mg (30.1%) of Example 499 as an off-white solid. MS-ESI: 446 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (s, 1H), 7.98 (s, 2H), 7.72 (s, 1H), 5.37 (s, 1H), 2.93 (t, J=7.4 Hz, 4H), 2.70 (t, J=7.7 Hz, 4H), 2.10-1.90 (m, 4H), 1.47 (s, 3H), 1.46 (s, 3H).

Example 500 (Compound 838)

2-Fluoro-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(pyrrolidin-3-yl)benzenesulfonimidamide (Scheme IX)

Step 1: 2-Fluoro-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(pyrrolidin-3-yl) benzenesulfonimidamide

To a stirred solution of tert-butyl 3-(3-fluoro-4-(N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)phenyl)pyrrolidine-1-carboxylate (272 mg, 0.50 mmol) in DCM (10 mL) in a 50-mL round-bottom flask was added BF₃.Et₂O (47% wt., 362 mg, 2.50 mmol) dropwise at 0° C. The resulting solution was stirred for 2 h at 0° C. The reaction was then quenched by the addition of 0.2 mL of sat. NaHCO₃ solution. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep OBD C18 Column, 30*150 mm, 5 um; mobile phase, water (10 mM NH₄HCO₃+0.1% NH₃.H₂O) and MeCN (10% to 33% Phase B over 7 min); Detector, UV (254/220 nm). This resulted in 90.8 mg (41.0%) of Example 500 as an off-white solid. MS-ESI: 443(M+1). ¹H NMR (300 MHz, MeOH-d₄) δ 7.98 (d, J=7.7 Hz, 1H), 7.45-7.25 (m, 2H), 6.91 (s, 1H), 3.82-3.56 (m, 3H), 3.50-3.10 (m, 2H), 2.90-2.65 (m, 8H), 2.60-2.30 (m, 2H), 2.10-1.90 (m, 4H).

TABLE 44 Example 501 and Example 502 in the following table were prepared using similar conditions as described in Example 500 and Scheme IX from the corresponding chiral Intermediate 128B and Intermediate 128A Exact Mass Ex. # Cmpd # Structure IUPAC Name [M + H]⁺ 501 838e

(S) or (R)-2-fluoro-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-4-(pyrrolidin-3-yl)benzenesulfonimidamide 443 502 838b

(R) or (S)-2-fluoro-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-4-(pyrrolidin-3-yl)benzenesulfonimidamide 443

Example 503 (Compound 832)

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(morpholinomethyl)benzenesulfonimidamide (Scheme X)

Step 1: N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(morpholinomethyl)benzene-sulfonimidamide

To a stirred solution of 3-formyl-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzene-sulfonimidamide (50 mg, 0.13 mmol) in DCE (5 mL) in a 25-mL round-bottom flask under nitrogen was added morpholine (33.9 mg, 0.39 mmol) at RT. The resulting solution was stirred overnight at RT. Then NaBH(OAc)₃ (55.1 mg, 0.26 mmol) was added to the mixture at 0° C. The resulting solution was stirred for 12 h at RT. The resulting solution was extracted with 3×10 mL of EtOAc and the organic layers were combined and dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1), further purified by Prep-HPLC with the following conditions: XBridge Prep OBD C18 Column, 30*150 mm, 5 um; mobile phase, water (10 mM NH₄HCO₃+0.1% NH₃.H₂O) and MeCN (10% to 33% Phase B over 7 min); Detector, UV (254/220 nm). This resulted in 27.9 mg (47.2%) of Example 503 as a yellow solid. MS-ESI: 455 (M+1).

TABLE 45 Examples in the following table were prepared using similar conditions as described in Example 503 and Scheme X from appropriate starting materials. Exact Mass Ex. # Cmpd # Structure IUPAC Name [M + H]⁺ 504 830

N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-3-(((2- methoxyethyl)(methypamino) methyl)benzenesulfonimidamide 457 505 825

N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-3- ((4-methylpiperazin-1-yl)methyl) benzenesulfonimidamide 468 506 824

3-(((2-(Dimethylamino)ethyl) (methyl)amino)methyl)-N′- ((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)benzenesulfonimidamide 470 507 823

3-(((Cyclopropylmethyl) (methyl)amino)methyl)-N′- ((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)benzenesulfonimidamide 453 508 848

N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-3- ((methylamino)methyl) benzenesulfonimidamide 399

Example 509 (Compound 8681)

(S)-N′-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide (Scheme 32)

To a stirred solution of (S)-5-(2-hydroxypropan-2-yl)-N′-((1-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiazole-2-sulfonimidamide (180 mg, 0.41 mmol) in EtOH (10 mL) in a 50-mL round-bottom flask was added NaBH₄ (31.3 mg, 0.828 mmol) in portions at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched with 5 mL of water. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep C18 OBD Column, 19*150 mm 5 um; mobile phase, water (10 mM NH₄HCO₃+0.1% NH₃.H₂O) and MeCN (5% to 24% Phase B over 7 min); Detector, UV 254 nm. This resulted in 130 mg (71.9%) of Example 509 as a white solid. MS-ESI: 437 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (br s, 1H), 7.79 (s, 1H), 7.65 (br s, 2H), 6.97 (s, 1H), 5.90 (s, 1H), 5.10 (d, J=5.6 Hz, 1H), 5.00-4.90 (m, 1H), 3.90-3.80 (m, 2H), 3.80-3.60 (m, 4H), 2.35-2.25 (m, 1H), 2.05-1.85 (m, 2H), 1.75-1.60 (m, 1H), 1.55 (s, 6H).

TABLE 46 Examples in the following table were prepared using similar conditions as described in Example 509 and Scheme 32 from appropriate chiral starting ketones Exact Mass Ex. # Cmpd # Structure IUPAC Name [M + H]⁺ 510 867f

(R)-N′-((3-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiazole-2- sulfonimidamide 437 511 867e

(S)-N′-((3-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiazole-2- sulfonimidamide 437 512 868e

(R)-N′-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiazole-2- sulfonimidamide 437

Example 513 (Compound 839)

5-(2-hydroxypropan-2-yl)-1-phenyl-N′-((8-propyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonimidamide (Scheme XI)

To a stirred solution of N′-((8-allyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonimidamide (20 mg, 0.038 mmol) in MeOH (10 mL) 50 mL round-bottom flask under nitrogen was added Pd/C (10% wt., 5.0 mg), the flask was excavated and flushed with hydrogen 3 times. The resulting mixture was stirred for 16 h at RT under hydrogen with a balloon. The resulting mixture was filtered; the filter cake was washed with MeOH (3×5 mL). The filtrate and wash were concentrated under reduced pressure. The crude product was purified by Prep-HPLC using the following conditions: XBridge Shield RP18 OBD Column 19*250 mm, 10 um; Mobile Phase A: water (10 mM NH₄HCO₃), Mobile Phase B: MeCN; Flow rate: 25 mL/min; Gradient: 50% B to 52% B in 10 min; 210/254 nm; Rt: 11.45 min. This resulted in Example 513 (6.5 mg, 32.4%) as a white solid. MS-ESI: 522 (M+1). ¹H NMR (400 MHz, MeOH-d₄) δ 7.60-7.48 (m, 5H), 6.87 (s, 1H), 2.84 (t, J=7.4 Hz, 4H), 2.82-2.70 (m, 4H), 2.57-2.48 (m, 2H), 2.08-1.96 (m, 4H), 1.60-1.45 (m, 2H), 1.45 (s, 3H), 1.44 (s, 3H), 0.95 (t, J=7.4 Hz, 3H).

TABLE 47 Example 514 was obtained from Step 3 in Route 2 in Example 224. Exact Mass Ex. # Cmpd # Structure IUPAC Name [M + H]⁺ 514 865a

(R)-N′-((6-(2-chloroethyl)-2,3-dihydro- 1H-inden-4-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamide 443/445

TABLE 48 Examples in the following table were obtained from chiral HPLC resolutions of racemic examples described above. The chiral column and eluents are listed in the table. As a convention, the faster-eluting enantiomer is always listed first in the table followed by the slower-eluting enantiomer of the pair. The symbol * at a chiral center denotes that this chiral center has been resolved and the absolute stereochemistry at that center has not been determined. Assigned stereochemistry in compound names are tentative. LC- MS Ex. Cmpd [M + # # Structure IUPAC Name Column Eluents H]⁺ 515 869a

(R,6R) or (S,6R)-N′- ((1,2,3,5,6,7- hexahydro- s-indacen-4- yl)carbamoyl)- 6-hydroxy-6,7- dihydro-5H- pyrazolo[5,1-b] [1,3]oxazine-3- sulfonimidamide CHIRALPAK ID, 2*25 cm, (5 um) EtOH in Hex (8 mM NH₃• MeOH)^(#) 418 516 869b

(S,6R) or (R,6R)-N′- ((1,2,3,5,6,7- hexahydro-s-indacen- 4-yl)carbamoyl)- 6-hydroxy-6,7- dihydro-5H- pyrazolo[5,1-b] [1,3]oxazine-3- sulfonimidamide CHIRALPAK ID, 2*25 cm, (5 um) EtOH in Hex (8 mM NH₃• MeOH) 418 517 809b

(S) or (R)-5- ((dimethylamino) methyl)- 3-fluoro-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)pyridine-2- sulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um EtOH in Hex (0.1% FA) 432 518 809a

(R) or (S)-5- ((dimethylamino) methyl)- 3-fluoro-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl) pyridine-2- sulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um EtOH in Hex (0.1% FA) 432 519 813b

(R) or (S)-N′- ((1,2,3,5,6,7-hexahydro- s-indacen-4-yl) carbamoyl)-4-(2- methyl-1-(methylamino) propan-2-yl) benzenesulfonimidamide CHIRALPAK ID, 2* 25 cm, (5 um) IPA in Hex:DCM = 5:1 (10 mM NH₃• MeOH) 441 520 813a

(S) or (R)-N′- ((1,2,3,5,6,7-hexahydro- s-indacen-4-yl) carbamoyl)-4-(2- methyl-1-(methylamino) propan-2-yl) benzenesulfonimidamide CHIRALPAK ID, 2* 25 cm, (5 um) IPA in Hex:DCM = 5:1 (10 mM NH₃• MeOH) 441 498 803b

(R) or (S)-N′- ((6-cyclopropyl-5- methyl-2,3-dihydro- 1H-inden-4- yl)carbamoyl)-4- (2-hydroxyprepan-2- yl)thiophene-2- sulfonimidamide Chiralpak ID, 2*25 cm, (5 um) 50% IPA in Hex (0.1% FA) 434 521 803a

(S) or (R)-N′-((6- cyclopropyl-5- methyl-2,3-dihydro- 1H-inden-4- yl)carbamoyl)-4- (2-hydroxyprepan-2- yl)thiophene-2- sulfonimidamide Chiralpak ID, 2*25 cm, (5 um) 50% IPA in Hex (0.1% FA) 434 522 806a

(R) or (S)- N′-((8-cyano- 1,2,3,5,6,7- hexahydro-s-indacen- 4-yl)carbamoyl)- 5-(2-hydroxypropan- 2-yl)pyridine-3- sulfonimidamide CHIRALPAK ID, 2*25 cm, (5 um) IPA in Hex (0.1% FA) 439 523 806b

(S) or (R)-N′- ((8-cyano- 1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)- 5-(2-hydroxypropan-2- yl)pyridine-3- sulfonimidamide CHIRALPAK ID, 2*25 cm, (5 um) IPA in Hex (0.1% FA) 439 524 808b

(R) or (S)-4-(azetidin- 1-ylmethyl)-2- fluoro-N′- ((2,4,5,6- tetrahydro-1H- cyclobuta[f]inden-3 - yl)carbamoyl) benzenesulfonimidamide CHIRALPAK IG, 2*25 cm, (5 um) EtOH in Hex (8 mM NH₃•MeOH) 429 525 808a

(S) or (R)-4-(azetidin- 1-ylmethyl)-2- fluoro-N′-((2,4,5,6- tetrahydro-1H- cyclobuta[f]inden-3 - yl)carbamoyl) benzenesulfonimidamide CHIRALPAK IG, 2*25 cm, (5 um) EtOH in Hex (8 mM NH₃•MeOH) 429 526 812b

(R) or (S)-2-(2- hydroxypropan-2-yl)- N′-((6-isopropyl-2,3- dihydro-1H- inden-5-yl) carbamoyl)thiazole-5- sulfonimidamide Chiralpak ID-2, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 423 527 812

(S) or (R)-2-(2- hydroxypropan-2-yl)- N′-((6-isopropyl-2,3- dihydro-1H-inden-5- yl)carbamoyl) thiazole-5- sulfonimidamide Chiralpak ID-2, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 423 528 810b

(R) or (S)-2-fluoro-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)- 4-(1-((methylamino) methyl)cyclopropyl) benzenesulfonimidamide CHIRALPAK IG, 2.0*25 cm, (5 um) EtOH in MTBE (10 mM NH₃•MeOH) 457 529 810a

(S) or (R)-2-fluoro-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)- 4-(1-((methylamino) methyl)cyclopropyl) benzenesulfonimidamide CHIRALPAK IG, 2.0*25 cm, (5 um) EtOH in MTBE (10 mM NH₃•MeOH) 457 530 811b

(R) or (S)-4-(2- hydroxypropan-2-yl)- N′-((3-oxo-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl) (thiophene-2- sulfonimidamide CHIRALPAK IG, 5*25 cm, 5 um EtOH in Hex (0.1% FA) 434 531 811a

(S) or (R)-4-(2- hydroxypropan-2-yl)- N′-((3-oxo-1,2,3,5,6,7- hexahydro- s-indacen-4- yl)carbamoyl) (thiophene-2 - sulfoniinidamide CHIRALPAK IG, 5*25 cm, 5 um EtOH in Hex (0.1% FA) 434 532 805a

(S) or (R)-N′- ((8-cyano- 1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)- 2-(2-hydroxypropan- 2-yl)-4- (methoxymethyl) thiazole-5- suifoiiimidamide CHIRAL ART Cellulose-SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 490 533 805b

(R) or (S)-N′-((8- cyano-1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl)- 2-(2-hydroxypropan- 2-yl)-4- (methoxymethyl) thiazole-5- sulfonimidamide CHIRAL ART Cellulose-SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 490 534 871b

(R,6R) or (S,6R)-6- methoxy-N′-((2,4,5,6- tetrahydro-1H- cyclobuta[f]inden-3- yl)carbamoyl)-6,7- dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3- sulfonimidamide CHIRALPAK ID, 2*25 cm, (5 um) EtOH in Hex:DCM = 5:1 (10 mM NH₃•MeOH) 418 535 871a

(S,6R) or (R,6R)-6- methoxy-N′-((2,4,5,6- tetrahydro-1H- cyclobuta[f]inden- 3-yl)caibamoyl)- 6,7-dihydro- 5H-pyrazolo [5,1-b][1,3]oxazine-3- sulfonimidamide CHIRALPAK ID, 2*25 cm, (5 um) EtOH in Hex:DCM = 5:1 (10 mM NH₃•MeOH) 418 536 814b

(S) or (R)-4- ((methylamino) methyl)-N′-((2,4,5,6- tetrahydro-1H- cyclobuta[f]inden-3- yl)carbamoyl) benzenesulfonimidamide chiralpak AS-H, 2*25 cm, (5 um) 43% IPA CO₂ 385 537 814a

(R) or (S)-4- ((methylamino) methyl)-N′-((2,4,5,6- tetrahydro-1H- cyclobuta[f]inden-3- yl)carbamoyl) benzenesulfonimidamide Chiralpak AS-H, 2*25 cm, (5 um) 43% IPA CO₂ 385 538 815b

(S) or (R)-3- fluoro-5-(2- hydroxypropan-2-yl)- N′-((3-oxo- 1,2,3,5,6,7- hexahydro- s-indacen-4- yl)carbamoyl) thiophene-2- sulfonimidamide CHIRALPAK AS-H, 2.0*25 cm, (5 um) 43% IPA CO₂ 452 539 815a

(R) or (S)-3- fluoro-5-(2- hydroxypropan- 2-yl)-N′-((3-oxo- 1,2,3,5,6,7-hexahydro- s-indacen-4- yl)carbamoyl) thiophene-2- sulfonimidamide CHIRALPAK AS-H, 2.0*25 cm, (5 um) 43% IPA CO₂ 452 540 866a

(S) or (R)-N′- ((8-cyano- 1,2,3,5,6,7-hexahydro- s-indacen-4- yl)carbamoyl)- 4-(2-hydroxypropan- 2-yl)thiazole-2- sulfonimidamide CHIRAL ART Cellulose-SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 446 541 866b

(R) or (S)-N′- ((8-cyano- 1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)- 4-(2-hydroxypropan- 2-yl)thiazole-2- sulfonimidamide CHIRAL ART Cellulose-SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 446 542 820b

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro-s-indacen- 4-yl)carbamoyl)- 4-(hydroxymethyl)- 2-(2-hydroxypropan- 2-yl)thiazole-5- sulfonimidamide CHIRAL ART Cellulose-SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 451 543 820a

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro- s-indacen- 4-yl)carbamoyl)- 4-(hydroxymethyl)- 2-(2-hydroxypropan- 2-yl)thiazole-5- sulfonimidamide CHIRAL ART Cellulose-SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 451 544 822b

(S) or (R)-N′- ((8-cyano- 1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)- 6-(2-hydroxypropan- 2-yl)pyridine-3- sulfonimidamide CHIRAL ART Cellulose-SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 440 545 822a

(R) or (S)-N′- ((8-cyano- 1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)- 6-(2-hydroxypropan- 2-yl)pyridine-3- sulfonimidamide CHIRAL ART Cellulose-SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 440 546 501b

(R) or (S)-N′-((2,4,5,6- tetrahydro- 1H-cyclobuta[f] inden-3-yl)carbamoyl)- 6,7-dihydio-5H- pyrazolo[5,1- b][1,3]oxazine-3- suIfonimidamide CHIRALPAK ID, 2*25 cm, (5 um) IPA in MTBE (0.1% FA) 388 547 501a

(S) or (R)-N′- ((2,4,5,6- tetrahydro- 1H-cyclobuta[f] inden-3-yl)carbamoyl)- 6,7-dihydio-5H- pyrazolo[5,1- b][1,3]oxazine-3- sulfonimidamide CHIRALPAK ID, 2*25 cm, (5 um) IPA in MTBE (0.1% FA) 388 548 817b

(R) or (S)-N′-((8-cyano- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- 5-(hydroxymethyl)-1- isopropyl-1H-pyrazole-3- sulfonimidamide CHIRALPAK IC, 2*25 cm, (5 um) EtOH in MTBE (0.1% FA) 443 549 817a

(S) or (R)-N′-((8-cyano- 1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)- 5-(hydroxymethyl)-1- isopropyl-1H- pyrazole-3- sulfonimidamide CHIRALPAK IC, 2*25 cm, (5 um) EtOH in MTBE (0.1% FA) 443 550 832b

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-3- (morpholinomethyl) benzenesulfonimidamide CHIRALPAK ID, 0.46*10 cm; 3 um EtOH in Hex (0.1% FA) 455 551 832a

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-3- (morpholinomethyl) benzenesulfonimidamide CHIRALPAK ID, 0.46*10 cm; 3 um EtOH in Hex (0.1% FA) 455 552 821a

(R) or (S)-N′- ((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)(2- 4-carbamoyl)- hydroxypropan-2-yl)-5- phenylthiophene-2-sulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um EtOH in Hex (0.1% FA) 496 553 821b

(S) or (R)-N′- ((1,2,3,5,6,7-hexahydro- s-indacen-4-yl) carbamoyl)-(4-2- hydroxypropan-2-yl)-5- phenylthiophene-2- sulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um EtOH in Hex (0.1% FA) 496 554 833b

(S) or (R)-5-fluoro-N′- ((1,2,3,5,6,7- hexahydro-s-indacen- 4-yl)carbamoyl)- 2-isopropylpyridine-4- sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 417 555 833a

(R) or (S)-5-fluoro-N′- ((1,2,3,5,6,7- hexahydro-s-indacen- 4-yl)carbamoyl)- 2-isopropylpyridine-4- sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 417 556 834b

(S) or (R)-N′- ((1,2,3,5,6,7-hexahydro- s-indacen-4-yl) carbamoyl)-2-(2- hydroxypropan-2- yl)thiazole-4- sulfonimidamide (R,R)- WHELK-O1- Kromasi, 5*25 cm (5 um) IPA in Hex (8 mM NH₃•MeOH) 421 557 834a

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro- s-indacen-4-yl) cartoamoyl)-2-(2- hydroxypropan-2- yl)thiazole-4- sulfoni midamide (R,R)- WHELK-O1- Kromasi, 5*25 cm (5 um) IPA in Hex (8 mM NH₃•MeOH) 421 558 413a

(R) or (S)-N′- ((1,2,3,5,6,7-hexahydro- 5-indacen-4-yl) carbamoyl)-6-methyl- 4,5,6,7-tetrahydrothieno [2,3-c]pyridine-2- sulfonimidamide Chiralpak ID, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 431 559 413b

(S) or (R)-N′- ((1,2,3,5,6,7-hexahydro- s-indacen-4-yl) carbamoyl)- 6-methyl-4,5,6,7- tetrahydrothieno[2,3- c]pyridine-2- sulfonimidamide Chiralpak ID, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 431 560 835b

(R) or (S)-4-(2- hydroxypropan-2- N′-((2,4,5,6- tetrahydro-1H- cyclobuta[f]inden-3 - y])carbamoyl) thiophene-2- sulfonimidamide CHIRALPAK IF, 2*25 cm, 5 um 40% MeOH (2 mM NH₃•MeOH) in CO₂ 406 561 835a

(S) or (R)-4-(2- hydroxypropan-2- N′-((2,4,5,6- tetrahydro-1H- cyclobuta[f]inden-3 - y])carbamoyl) thiophene-2- sulfonimidamide CHIRALPAK IF, 2*25 cm, 5 um 40% MeOH (2 mM NH₃•MeOH) in CO₂ 406 562 836b

(S) or (R)-N′- ((6-cyclopropyl-5- methyl-2,3-dihydro- 1H-inden-4- yl)carbamoyl)-2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide CHIRALPAK ID, 2*25 cm, (5 um) EtOH in MTBE (10 mM NH₃•MeOH) 435 563 836a

(R) or (S)-N′- ((6-cyclopropyl-5- methyl-2,3-dihydro- 1H-inden-4- yl)carbamoyl)-2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide CHIRALPAK ID, 2*25 cm, (5 um) EtOH in MTBE (10 mM NH₃•MeOH) 435 564 837b

(S) or (R)-2-(2- hydroxypropan-2-yl)- N′-((1-oxo-1,2,3,6,7, 8-hexahydro-as- indacen-4-yl) carbamoyl) thiazole-5- sulfonimidamide CHIRALPAK IA, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 435 565 837a

(R) or (S)-2-(2- hydroxypropan-2-yl)- N′-((1-oxo-1,2,3,6,7, 8-hexahydro-as- indacen-4-yl) carbamoyl) thiazole-5- sulfonimidamide CHIRALPAK IA, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 435 566 828a

(R) or (S)-N′-((8-allyl- 1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)- 5-(2-hydroxypropan- 2-yl)-1-phenyl- 1H-pyrazole-3- sulfonimidaimde CHIRALPAK IC, 2*25 cm, 5 um IPA in MTBE (0.1% FA) 520 567 828b

(S) or (R)-N′-((8-allyl- 1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)- 5-(2-hydroxypropan- 2-yl)-1-phenyl- 1H-pyrazole-3- sulfonimidaimde CHIRALPAK IC, 2*25 cm, 5 um IPA in MTBE (0.1% FA) 520 568 873b

(S) or (R)-N′- ((1,2,3,5,6,7-hexahydro- s-indacen-4-yl) carbamoyl)-6,7- dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-3- sulfonimidamide Chiralpak AD-H, 2*25 cm (5 um) 50% EtOH (2 mM NH₃•MeOH) in CO₂ 402 569 873a

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro- s-indacen-4-yl) caramoyl)-6,7- dihydro-5H- pyrazolo[5,1 - b][1,3]oxazine-3- sulfonimidamide Chiralpak AD-H, 2*25 cm (5 um) 50% EtOH (2 mM NH₃•MeOH) in CO₂ 402 570 412a

(R) or (S)-3-fluoro-N′- ((1,2,3,5,6,7- hcxahydro-s-indacen-4- yl)carbamoyl)-5- ((methylamino)methyl) thiophene-2- sulfonimidamide CHIRALPAK ID, 2*25 cm, (5 um) 40% MeOH:DC M = 1:1 (2 mM NH₃•MeOH) in CO₂ 423 571 412b

(S) or (R)-3-fluoro-N′- ((1,2,3,5,6,7- hcxahydro-s-indacen-4- yl)carbamoyl)-5- ((methylamino)methyl) thiophene-2- sulfonimidamide CHIRALPAK ID, 2*25 cm, (5 um) 40% MeOH:DC M = 1:1 (2 mM NH₃•MeOH) in CO₂ 423 572 840b

(R) or (S)-5-(2- hydroxypiopan-2-yl)- N′-((3-oxo-1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl)thiazole-2- sulfonimidamide CHIRALPAK AS-H, 2*25 cm, (5 um) 40% IPA (2 mM NH₃•MeOH) in CO₂ 435 573 540a

(S) or (R)-5-(2- hydroxypiopan-2-yl)- N′-((3-oxo-1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl)thiazole-2- sulfonimidamide CHIRALPAK AS-H, 2*25 cm, (5 um) 40% IPA (2 mM NH₃•MeOH) in CO₂ 435 574 844b

(S) or (R)-N′-((8-cyano- 1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-5-(2- hydroxypropan-2-yl)-1- pheny-1H-pyrazole-3- sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um IPA in MTBE (0.1% FA) 505 575 844a

(R) or (S)-N′-((8-cyano- 1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-5-(2- hydroxypropan-2-yl)-1- pheny-1H-pyrazole-3- sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um IPA in MTBE (0.1% FA) 505 576 841b

(R) or (S)-4- (difluoromethoxy)-N′- ((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl) benzenesulfonimidamide CHIRALPAK IG, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 422 577 841a

(S) or (R)-4- (difluoromethoxy)-N′- ((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl) benzenesulfonimidamide CHIRALPAK IG, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 422 578 849b

(R) or (S)-3-cyano-N′- ((8-cyano-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-5-(2- hydroxypropan-2-yl) benzenesulfonimidamide CHIRALPAK IC, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 464 579 849a

(S) or (R)-3-cyano-N′- ((8-cyano-1,2,3,5,6,7- hexahydro-5-indacen-4- yl)carbamoyl)-5-(2- hydroxypropan-2-yl) benzenesulfonimidamide CHIRALPAK IC, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 464 580 846b

(R) or (S)-4- ((dimethylamino)methyl)- N′-((2,4,5,6-tetrahydro- 1H-cyclobuta[f]inden-3 - yl)carbamoyl) benzenesulfonimidamide Chiralpak ID, 2*25 cm (5 um) EtOH in Hex (8 mM NH₃•MeOH) 399 581 846a

(S) or (R)-4- ((dimethylamino)methyl)- N′-((2,4,5,6-tetrahydro- 1H-cyclobuta[f]inden-3- yl)carbamoyl) benzenesulfonimidamide Chiralpak ID, 2*25 cm (5 um) EtOH in Hex (8 mM NH₃•MeOH) 399 582 845a

(R) or (S)-4- ((dimethylamino)methyl)- N′-(tricyclo[6.2.0.03,6] deca-1,3(6),7-trien-2- ylcarbamoyl) benzenesulfonimidamide CHIRALPAK ID, 2*25 cm, 5 um 30% EtOH in Hex (0.1% DEA) 385 583 845b

(S) or (R)-4- ((dimethylamino)methyl)- N′-(tricyclo[6.2.0.03,6] deca-1,3(6),7-trien-2- ylcarbamoyl) benzenesulfonimidamide CHIRALPAK ID, 2*25 cm, 5 um 30% EtOH in Hex (0.1% DEA) 385 584 349b

(S) or (R)-N′- ((1,2,3,5,6,7-hexahydro- s-indacen-4-yl) carbamoyl)- 2-methyl- 1,2,3,4- tetrahydroisoquinoline-7- sulfonimidamide (R.R) Whelk, 21.1* 250 mm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 425 585 349a

(R) or (S)-N′- ((1,2,3,5,6,7-hexahydro- s-indacen-4-yl) carbamoyl)- 2-methyl- 1,2,3,4- tetrahydroisoquinoline-7- sulfonimidamide (R.R) Whelk, 21.1* 250 mm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 425 586 850b

(S) or (R)-6- cyclopentyl-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl)pyridine-3- sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 425 587 850a

(R) or (S)-6- cyclopentyl-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl)pyridine-3- sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 425 588 851b

(S) or (R)-5-(2- hydroxypropan-2-yl)- N′-((1-oxo- 1,2,3,5,6,7-hexahydro-s- indacen-4- yl)carbamoyl) thiazole-2- sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 435 589 851a

(R) or (S)-5-(2- hydroxypropan-2-yl)- N′-((1-oxo- 1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbaamoyl) thiazole-2- sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 435 590 852b

(S) or (R)-N′- ((1,2,3,6,7,8- hexahydro- as-indacen-4-yl) carbamoyl)-6-(2- hydroxypropan-2- yl)pyridine-3- sulfonimidamide (R,R) Whelk, 21.1* 250 mm, 5 um EtOH in Hex (0.1% FA) 415 591 852a

(R) or (S)-N′- ((1,2,3,6,7,8- hexahydro- as-indacen-4-yl) carbamoyl)-6-(2- hydro\ypropan-2- yl)pyridine-3- sulfonimidamide (R.R) Whelk, 21.1* 250 mm, 5 um EtOH in Hex (0.1% FA) 415 592 853b

(S) or (R)-2-fluoro-N′- ((1,2,3,5,6,7- hexahydro-s-indacen- 4-yl)carbamoyl)- 4-(2-(methylamino) propan-2-yl) benzenesulfonimidamide (R.R) Whelk, 21.1* 250 mm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 445 593 853a

(R) or (S)-2-fluoro-N′- ((1,2,3,5,6,7- hexahydro-s-indacen- 4-yl)carbamoyl)- 4-(2-(methylamino) propan-2-yl) benzenesulfonimidamide (R.R) Whelk, 21.1* 250 mm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 445 594 855b

(S) or (R)-6- (difluoromethyl)-N′- ((1,2,3,5,6,7- hexahydroxy- indacen-4- yl)carbamoyl) pyridine-3- sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 407 595 855a

(R) or (S)-6- (difluoromethyl)-N′- ((1,2,3,5,6,7- hexahydroxy- indacen-4- yl)carbamovl)pyridine-3- sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 407 596 857b

(S) or (R)-N′-((8-chloro- 1,2,3,5,6,7- hexahydro-s-indacen- 4-yl)carbamoyl)- 2-(2-hydroxypropan- 2-yl)thiazole-5- sulfonimidamide Chiralpak ID, 2*25 cm, 5 um IPA in MTBE (10 mM NH₃•MeOH) 455/ 457 597 857a

(R) or (S)-N′-((8-chloro- 1,2,3,5,6,7- hexahydro-s-indacen- 4-yl)carbamoyl)- 2-(2-hydroxypropan- 2-yl)thiazole-5- sulfonimidamide Chiralpak ID, 2*25 cm, 5 um IPA in MTBE (10 mM NH₃•MeOH) 455/ 457 598 858b

(R) or (S)-4-(2- hydroxypropan-2-yl)- N′-((1-oxo-1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl) thiophene-2- sulfonimidamide CHIRALPAK IE, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 434 599 858a

(S) or (R)-4-(2- hydroxypropan-2-yl)- N′-((1-oxo-1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl) thiophene-2- sulfonimidamide CHIRALPAK IE, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 434 600 859b

(R) or (S)-3- fluoro-5-(2- hydroxypropan- 2-yl)-N′-((1-oxo- 1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)thiophene- 2-sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 452 601 859a

(S) or (R)-3- fluoro-5-(2- hydroxypropan- 2-yl)-N′-((1-oxo- 1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)thiophene- 2-sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (0.1% FA) 452 602 860b

(R) or (S)-N′- ((1,2,3,5,6,7-hexahydro- s-indacen-4-yl) carbamoyl)-4-(2- (methylamino) propan-2-yl) benzenesuIfonimidamide CHIRALPAK IG, 20*250 mm, 5 um IPA in MTBE (10 mM NH₃•MeOH) 427 603 860a

(R) or (S)-N′- ((1,2,3,5,6,7-hexahydro- s-indacen-4-yl) carbamoyl)-4-(2- (methylamino) propan-2-yl) benzenesulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um IPA in MTBE (10 mM NH₃•MeOH) 427 604 377b

(S) or (R)-4-((dimethylamino) methyl)- 3-fluoro-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl) benzenesulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 431 605 377a

(R) or (S)-4- ((dimethylamino) methyl)- 3-fluoro-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl) benzenesulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 431 606 344a

(R) or (S)-4- ((dimethylamino) methyl)- N′-((1,2,3,5,6,7- hexahydro-s-indacen- 4-yl)carbamoyl)-2- methoxybenzene- sulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um EtOH in Hex (2 mM NH₃) 443 607 344b

(S) or (R)-4- ((dimethylamino) methyl)- N′-((1,2,3,5,6,7- hexahydro-s-indacen- 4-yl)carbamoyl)-2- methoxybenzene- sulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um EtOH in Hex (2 mM NH₃) 443 608 861b

(R) or (R)-N′- ((1,2,3,5,6,7- hexahydro- s-indacen-4-yl) carbamoyl)-4- ((methyl(2,2,2- trifluoroethyl) amino)methyl) benzenesulfonimidamide CHIRALPAK IG, 2*25 cm (5 um) EtOH in Hex (8 mM NH₃•MeOH) 481 609 861a

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro- s-indacen-4-yl) carbamoyl)-4- ((methyl(2,2,2- trifluoroethyl) amino)methyl) benzenesulfonimidamide CHIRALPAK IC, 2*25 cm (5 um) EtOH in Hex (8 mM NH₃•MeOH) 481 610 322a

(R) or (S)-4-(((2,2- difluoroethyl) (methyl)amino)methyl)- N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl) benzenesulfonimidamide CHIRALPAK IF, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 463 611 322b

(S) or (R)-4-(((2,2- difluoroethyl) (methyl)amino)methyl)- N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl) benzenesulfonimidamide CHIRALPAK IF, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 463 612 862b

(R) or (S)-N′-((1,2,3,5,6,7- hexahydro- s-indacen-4- yl)carbamoyl) benzenesulfonimidamide CHIRALPAK IA, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 356 613 862a

(S) or (R)-N′-((1,2,3,5,6,7- hexahydro- s-indacen-4- yl)carbamoyl) benzenesulfonimidamide CHIRALPAK IA, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 356 614 863b

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro- s-indacen-4- yl)carbamoyl)-4- (isopropyl(methyl) amino) benzenesulfonimidamide (R.R) Whelk, 21.1* 250 mm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 427 615 863a

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro- s-indacen-4- yl)carbamoyl)-4- (isopropyl(methyl) amino) benzenesulfonimidamide (R.R) Whelk, 21.1* 250 mm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 427 616 355b

(S) or (R)-6- ((dimethylamino) methyl)- N′-((1,2,3,5,6,7- hexahydro-s-indacen- 4-yl)carbamoyl) pyridine-3- sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 414 617 355a

(R) or (S)-6- ((dimethylamino) methyl)- N′-((1,2,3,5,6,7- hexahydro-s-indacen- 4-yl)carbamoyl) pyridine-3- sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 414 618 356b

(S) or (R)-N′- ((1,2,3,5,6,7- hexahydro- s-indacen-4-yl) carbamoyl)-4- isobutylbenzene- sulfonimidamide CHIRALPAK IF, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 412 619 356a

(R) or (S)-N′- ((1,2,3,5,6,7- hexahydro- s-indacen-4-yl) carbamoyl)-4- isobutylbenzene- sulfonimidamide CHIRALPAK IF, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 412 620 346a

(R) or (S)-4-((3,3- difluoropymolidin-1- yl)methyl)-N′- ((1,2,3,5,6,7- hexahydro- s-indacen-4- yl)carbamoyl) benzenesulfonimidamide CHIRALPAK IF, 2*25 cm, 5 um EtOH in Hex 475 621 346b

(S) or (R)-4-((3,3- difluoropymolidin-1- yl)methyl)-N′- ((1,2,3,5,6,7- hexahydro- s-indacen-4- yl)carbamoyl) benzenesulfonimidamide CHIRALPAK IF, 2*25 cm, 5 um EtOH in Hex 475 622 838f

(R,S) or (S,S)- 2-fluoro-N′- ((1,2,3,5,6,7- hexahydro- s-indacen-4- yl)carbamoyl)-4- pyrrolidin-3-yl) benzenesulfonimidamide CHIRALPAK IC, 2*25 cm, 5 um; from Ex. 501 IPA in Hex (0.1% FA) 443 623 838d

(S,S) or (R,S)- 2-fluoro-N′- ((1,2,3,5,6,7-hexahydro- s-indacen-4- yl)carbamoyl)-4-(- pyrrolidin-3-yl) benzenesulfonimidamide CHIRALPAK IC, 2*25 cm, 5 um; from Ex. 501 IPA in Hex (0.1% FA) 443 624 838c

(R,R) or (S,R)- 2-fluoro-N′- ((1,2,3,5,6,7-hexahydro- s-indacen-4- yl)carbamoyl)-4- pyrrolidin-3-yl) benzenesulfonimidamide CHIRALPAK IC, 2*25 cm, 5 um; from Ex. 502 EtOH in MTBE (0.1% FA) 443 625 838a

(S,R) or (R,R)- 2-fluoro-N′- ((1,2,3,5,6,7-hexahydro- s-indacen-4- yl)carbamoyl)-4- pyrrolidin-3-yl) benzenesulfonimidamide CHIRALPAK IC, 2*25 cm 5 um; from Ex. 502 EtOH in MTBE (0.1% FA) 443 626 829b

(R,R) and (S,R)- 2-(1,2-dihydroxypropan- 2-yl)-N′-((l,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl) thiazole-5- sulfonimidamide (mixture of two isomers) 1^(st) and 2^(nd) peak CHIRALPAK IF, 2*25 cm 5 um; from Ex. 436 EtOH in Hex (0.1% FA) 437 627 829c

(R,S) or (S,S)-1,2- dihydroxypropan-2- yl)-N′-((l,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl) thiazole-5- sulfonimidamide 3^(rd) peak CHIRALPAK IF, 2*25 cm, 5 um; from Ex. 436 EtOH in Hex (0.1% FA) 437 628 829a

(S,S) or (R,S)-1,2- dihydroxypropan-2- yl)-N′-((l,2,3,5,6,7-hexahydro-s- indacen-4-yl) carbamoyl) thiazole-5- sulfonimidamide 4^(th) peak CHIRALPAK IF, 2*25 cm 5 um; from Ex. 436 EtOH in Hex (0.1% FA) 437 629 411a

(S,R) or (R,R)-N′- ((8-cyano- 1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-5-(1,2- dihydroxypropan- 2-yl)-3- fluorothiophene-2- sulfonimidamide 1^(st) peak CHIRALPAK IG, 20*250 mm, 5 um; from Ex. 443 EtOH in Hex (0.1% FA) 479 630 411b

(R,R) or (S,R)-N′- ((8-cyano- 1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-5-(1,2- dihydroxypropan- 2-yl)-3- fluorothiophene-2- sulfonimidamide 2^(nd) peak CHIRALPAK IG, 20*250 mm, 5 um; from Ex. 443 EtOH in Hex (0.1% FA) 479 631 411e

(R,S) and (S,S)- N′-((8-cyano- 1,2,3,5,6,7-hexahydro- s-indacen-4- yl)carbamoyl)-5-(1,2- dihydroxypropan- 2-yl)-3- fluorothiophene-2- sulfonimidamide 3^(rd) and 4^(th) peak CHIRALPAK IG, 20*250 mm, 5 um; from Ex. 443 EtOH in Hex (0.1% FA) 479 632 411d

(S,S) and (R,S)- N′-((8-cyano- 1,2,3,5,6,7-hexahydro- s-indacen-4- yl)carbamoyl)-5-(1,2- dihydroxypropan- 2-yl)-3- fluorothiophene-2- sulfonimidamide 1st peak CHIRALPAK IC, 2*25 cm, 5 um; from Ex. 631 EtOH in Hex (0.1% FA) 479 633 411c

(R,S) and (S,S)- N′-((8-cyano- 1,2,3,5,6,7-hexahydro- s-indacen-4- yl)carbamoyl)-5-(1,2- dihydroxypropan- 2-yl)-3- fluorothiophene-2- sulfonimidamide 2^(nd) peak CHIRALPAK IC, 2*25 cm, 5 um; from Ex. 631 EtOH in Hex (0.1% FA) 479 634 842a

(R,R) and (S,R)-N′- ((8-cyano- 1,2,3,5,6,7- hexahydro-s- indacen-4-yl) carbamoyl)-2-(1,2- dihydroxypropan-2-yl)thiazole-5- sulfonimidamide (mixture of two isomers) 1^(st) and 2^(nd) peak CHIRALPAK IE, 2*25 cm, 5 um; from Ex. 437 EtOH in Hex (0.1% FA) 462 635 842b

(R,S) and (S,S)-N′- ((8-cyano- 1,2,3,5,6,7- hexahydro- indacen-4-yl) carbamoyl)-2-(1,2- dihydroxypropan-2-yl)thiazole-5- sulfonimidamide (mixture of two isomers) 3^(rd) and 4^(th) peak CHIRALPAK IE, 2*25 cm, 5 um; from Ex. 437 EtOH in Hex (0.1% FA) 462 636 842d

(S,R) or (R,R)-N′- ((8-cyano- 1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-2-(1,2- dihydroxypropan-2-yl)thiazole-5- sulfonimidamide 1^(st) peak Chiralpak IA, 2*25 cm, 5 um; from Ex. 634 IPA in Hex (0.1% FA) 462 637 842c

(R,R) or (S,R)-N′- ((8-cyano- 1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-2-(1,2- dihydroxypropan-2-yl)thiazole-5- sulfonimidamide 2^(nd) peak Chiralpak IA, 2*25 cm, 5 um; from Ex. 634 IPA in Hex (0.1% FA) 462 638 826f

(R,R) and (S,R)-4-(1- (difluoromethoxy) ethyl)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl) benzenesulfonimidamide (mixture of two isomers) 1^(st) and 2^(nd) peak CHIRALPAK IG, 2*25 cm (5 um); from Ex. 452 EtOH in Hex (8 mM NH₃•MeOH) 450 639 826d

(R,S) and (S,S)-4-(1- (difluoromethoxy) ethyl)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl) benzenesulfonimidamide (mixture of two isomers) 3^(rd) and 4^(th) peak CHIRALPAK IG, 2*25 cm (5 um); from Ex. 452 EtOH in Hex (8 mM NH₃•MeOH) 450 640 826b

(S,R) and (R,R)-4-(1- (difluoromethoxy) ethyl)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl) benzenesulfonimidamide 1^(st) peak CHIRALPAK IA, 2*25 cm, 5 um; from Ex. 638 EtOH in MTBE (10 mM NH₃•MeOH) 450 641 826a

(R,R) and (S,R)-4-(1- (difluoromethoxy) ethyl)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl) benzenesulfonimidamide 2^(nd) peak CHIRALPAK IA, 2*25 cm, 5 um; from Ex. 638 EtOH in MTBE (10 mM NH₃•MeOH) 450 642 826e

(S,S) and (R,S)-4-(1- (difluoromethoxy) ethyl)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl) benzenesulfonimidamide 1^(st) peak CHIRALPAK IG, 20*250 mm, 5 um; from Ex. 639 IPA in Hex (0.1% FA) 450 643 826c

(R,S) and (S,S)-4-(-1- (difluoromethoxy) ethyl)-N′- ((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl) benzenesulfonimidamide 2^(nd) peak CHIRALPAK IG, 20*250 mm, 5 um; from Ex. 639 IPA in Hex (0.1% FA) 450 644 819d

  (R,R) or (S,R)-4-(-1- (dimethylamino)- 2,2-difluoroethyl)-N′- ((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl) benzenesulfonimidamide Column 2: Chiralpak ID, 2*25 cm, 5 um, IPA in Hex (0.1% FA) to separate two fast-co-cluting isomers from Column 1 CHIRALPAK IG, 2*25 cm (5 um), EtOH in Hex (0.1% FA) 463 645 819c

(S,S) or (R,S)-4-(-1- (dimethylamino)- 2,2-difluoroethyl)-N′- ((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl) benzenesulfonimidamide 863 646 819b

  (R,S) or (S,S)-4-(-1- (dimethylamino)- 2,2-difluoroethyl)-N′- ((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl) benzenesulfonimidamide Column 2: Chiralpak ID, 2*25 cm, 5 um, IPA in Hex (0.1% FA) to separate two slow-co-cluting isomers from Column 1 CHIRALPAK IG, 2*25 cm (5 um), EtOH in Hex (0.1% FA) 463 647 819a

(S,R) or (R,R)-4-(1- (dimethylamino)- 2,2-difluoroethyl)-N′- ((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl) benzenesulfonimidamide 463 648 847b

(R,R) or (S,R)-N′- ((1,2,3,5,6,7- hexahydro- s-indacen-4-yl)carbamoyl)- 4-(pyrrolidin-2-yl) benzenesulfonimidamide 1^(st) peak Ultimate Diol, 20*250 mm, 5 um; 35% MeOH (2 mM NH₃) in CO₂ 425 649 847a

(S,R) or (R,R) and (S,S) or (R,S)-N′- ((1,2,3,5,6,7- hexahydro-s-indacen- 4-yl)carbamoyl)-4- (pyrrolidin-2-yl) benzenesulfonimidamide (mixture of two isomers) 2^(nd) and 3^(rd) peak Ultimate Diol, 20*250 mm, 5 um; 35% MeOH (2 mM NH₃) in CO₂ 425 650 847b

(R,S) or (S,S)-N′- ((1,2,3,5,6,7- hexahydro-s-indacen- 4-yl)carbamoyl)- 4-(pyrrolidin-2-yl) benzenesulfonimidamide 4^(th) peak Ultimate Diol, 20*250 mm, 5 um; 35% MeOH (2 mM NH₃) in CO₂ 425 651 867d

(R,S) or (R,R)-N′- ((3-hydroxy- 1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiazole-2- sulfonimidamide 1^(st) peak CHIRAL ART Cellulose- SB, 2*25 cm (5 um); from Ex. 510 35% IPA (2 mM NH₃•MeOH) in CO₂ 437 652 867c

(R,R) or (R,S)-N′- ((3-hydroxy- 1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiazole-2- sulfonimidamide 2^(nd) peak CHIRAL ART Cellulose- SB, 2*25 cm (5 um); from Ex. 510 35% IPA (2 mM NH₃•MeOH) in CO₂ 437 653 867b

(S,S) or (S,R)-N′- ((3-hydroxy- 1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiazole-2- sulfonimidamide 1^(st) peak CHIRALPAK AS, 2*25 cm, (5 um); from Ex. 511 30% IPA (2 mM NH₃•MeOH) in CO₂ 437 654 867a

(S,R) or (S,S)-N′- ((-3-hydroxy- 1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiazole-2- sulfonimidamide 2^(nd) peak CHIRALPAK AS, 2*25 cm, (5 um); from Ex. 511 30% IPA (2 mM NH₃) in CO₂ 437 655 868d

(S,R) or (S,S)-N′- ((1-hydroxy- 1,2,3,5,6,7- hexahydro-5- indacen-4- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiazole-2- sulfonimidamide 1^(st) peak Chiralpak AD, 2*25 cm, (5 um); from Ex. 509 35% MeOH (2 mM NH₃) in CO₂ 437 656 868c

(S,S) or (S,R)-N′- ((1-hydroxy- 1,2,3,5,6,7- hexahydro-5- indacen-4- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiazole-2- sulfonimidamide 2^(nd) peak Chiralpak AD, 2*25 cm, (5 um); from Ex. 509 35% MeOH (2 mM NH₃) in CO₂ 437 657 868b

(R,R) or (R,S)-N′-((1- hydroxy- 1,2,3,5,6,7- hexahydro-5- indacen-4- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiazole-2- sulfonimidamide 3^(rd) peak Chiralpak AD, 2*25 cm, (5 um); from Ex. 512 40% MeOH (2 mM NH₃) in CO₂ 437 658 868a

(R,S) or (R,R)-N′-((1- hydroxy- 1,2,3,5,6,7- hexahydro-5- indacen-4- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiazole-2- sulfonimidamide 4^(th) peak Chiralpak AD, 2*25 cm, (5 um); from Ex. 512 40% MeOH (2 mM NH₃) in CO₂ 437 659 854d

(R,S) and (S,S)-4- (cyclopropyl (dimethylamino) methyl)-N′- ((1,2,3,5,6,7- hexahydro- s-indacen-4-yl) carbamoyl) benzenesulfonimidamide (mixture of two isomers) 1^(st) peak CHIRAL ART Cellulose- SB, 2*25 cm, 5 um IPA in Hex (8 mM NH₃•MeOH) 453 660 854c

(R,R) and (S,R)-4- (cyclopropyl (dimethylamino) methyl)-N′- ((1,2,3,5,6,7- hexahydro- s-indacen-4-yl) carbamoyl) benzenesulfonimidamide (mixture of two isomers) 2^(nd) peak CHIRAL ART Cellulose- SB, 2*25 cm, 5 um IPA in Hex (8 mM NH₃•MeOH) 453 661 854b

(S,R) and (R,R)-4- (cyclopropyl (dimethylamino) methyl)-N′- ((1,2,3,5,6,7- hexahydro- s-indacen-4-yl) carbamoyl) benzenesulfonimidamide (mixture of two isomers) 1^(st) peak Chiralpak IG, 2*25 cm, 5 um; from Ex. 660 EtOH in Hex (8 mM NH₃•MeOH) 453 662 854a

(R,R) and (S,R)-4- (cyclopropyl (dimethylamino) methyl)-N′- ((1,2,3,5,6,7- hexahydro- s-indacen-4-yl) carbamoyl) benzenesulfonimidamide (mixture of two isomers) 2^(nd) peak Chiralpak IG, 2*25 cm, 5 um; from Ex. 660 EtOH in Hex (8 mM NH₃•MeOH) 453 663 864

(R,S) and (S,S)-4-(1- (dimethylamino)- 2,2,2-trifluoroethyl)- N′-((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl) benzenesulfonimidamide (mixture of two isomers) 1^(st) peak CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 481 664 856e

(R,R) and (S,R)-4-(1- (dimethylamino)- 2,2,2-trifluoroethyl)- N′-((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl) benzenesulfonimidamide (mixture of two isomers) 2^(nd) peak CHIRAL ART Cellulose- SB, 2*25 cm, 5 um EtOH in Hex (8 mM NH₃•MeOH) 481 665 856d

(S,S) or (R,S)-4-(1- (dimethylamino)- 2,2,2-trifluoroethyl)- N′-((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl) benzenesulfonimidamide 1^(st) peak Chiralpak IG, 2*25 cm, 5 um; from Ex. 663 EtOH in MTBE (10 mM NH₃•MeOH) 481 666 856c

(R,S) or (S,S)-4-(1- (dimethylamino)- 2,2,2-trifluoroethyl)- N′-((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl) benzenesulfonimidamide 2^(nd) peak Chiralpak IA, 2*25 cm, 5 um; from Ex. 663 EtOH in MTBE (10 mM NH₃- MeOH) 481 667 856b

(S,R) or (R,R)-4- (1-(dimethylamino)-2,2,2- trifluoroethyl)- N′-((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl) benzenesulfonimidamide 1^(st) peak Chiralpak IA, 2*25 cm, 5 um; from Ex. 664 EtOH in MTBE (10 mM NH₃•MeOH) 481 668 856

(R,R) or (S,R)-4- (1-(dimethylamino)-2,2,2- trifluoroethyl)- N′-(( 1,2,3,5,6,7- hexahydro-s-indacen- 4-yl)carbamoyl) benzenesulfonimidamide 2^(nd) peak Chiralpak IA, 2*25 cm, 5 um; from Ex. 664 EtOH in MTBE (10 mM NH₃•MeOH) 481 ^(#)The amount of NH₃ in this chiral chromatographic solvent and similar solvents were adjusted by adding 2 M NH₃ in MeOH to the desired NH³ concentration. In this case, the resulting concentration of NH₃ in MeOH is 8 mM.

Example 669 (Compound 901)

3-Fluoro-5-((methylamino)methyl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)thiophene-2-sulfonimidamide (Scheme XII) Examples 670 (Compound 901a) and Examples 671 (Compound 901b)

Examples 670 and 671 (Stereochemistry Not Assigned) (S)- and (R)-3-Fluoro-5-((methylamino)methyl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)thiophene-2-sulfonimidamide

Step 1: Tert-butyl((5-(N-(tert-butyldimethylsilyl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl) carbamoyl)sulfamidimidoyl)-4-fluorothiophen-2-yl)methyl)(methyl)carbamate

To a stirred solution of tert-butyl ((5-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)-4-fluorothiophen-2-yl) methyl)(methyl)carbamate (200 mg, 0.46 mmol) in THF (5.0 mL) in a 25-mL round-bottom flask was added DBU (139 mg, 0.91 mmol) at RT, followed by the addition of 3-isocyanato-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (85 mg, 0.46 mmol) in THF (3 mL) dropwise at 0° C. The resulting solution was stirred overnight at RT. The reaction was quenched with water (5 mL). The resulting solution was extracted with 3×10 mL ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 180 mg (crude) of the title compound as a white solid. MS-ESI: 538 (M+1).

Step 2: 3-Fluoro-5-((methylamino)methyl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl) carbamoyl)thiophene-2-sulfonimidamide

To a stirred solution of tert-butyl ((5-(N-(tert-butyldimethylsilyl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f] inden-3-yl)carbamoyl)sulfamidimidoyl)-4-fluorothiophen-2-yl)methyl)(methyl)carbamate (180 mg, crude) in THF (5 mL) in a 25-mL round-bottom flask was added HCl in 1,4-dioxane (4 M, 5.0 mL) dropwise at 0° C. The resulting solution was stirred overnight at RT. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep OBD C18 Column, 30*150 mm 5 um; mobile phase, water (10 mM NH₄HCO₃+0.1% NH₃.H₂O) and ACN (20% to 30% Phase B over 7 min); Detector, UV 254/210 nm. This resulted in 65 mg (34.8% over two steps) of Example 669 as a white solid. MS-ESI: 424 (M+1). ¹H NMR (300 MHz, DMSO-d₆) δ 8.26 (br s, 1H), 6.93 (s, 1H), 6.66 (s, 1H), 3.79 (s, 2H), 3.00-2.94 (m, 2H), 2.92-2.85 (m, 2H), 2.83-2.67 (m, 4H), 2.29 (s, 3H), 1.96-1.83 (m, 2H).

Step 3: Chiral Separation

Example 669 (60 mg) was resolved by Prep-Chiral-HPLC with the following conditions: CHIRALPAK ID, 2*25 cm(5 um); Mobile Phase A: Hex:DCM=3:1(10 mM NH₃-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 30% B to 30% B over 23 min; Detector: UV 254/220 nm. Rt₁: 6.2 (Example 670); Rt₂: 9.46 (Example 671). This resulted in 22.1 mg (99% ee) of (Example 670) as a white solid. This resulted in 22.3 mg (99% ee) of (Example 671) as a white solid.

Example 670 MS-ESI: 424 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (br s, 1H), 6.92 (s, 1H), 6.65 (s, 1H), 3.78 (s, 2H), 3.00-2.94 (m, 2H), 2.91-2.84 (m, 2H), 2.83-2.64 (m, 4H), 2.29 (s, 3H), 1.95-1.85 (m, 2H).

Example 671 MS-ESI: 424 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (br s, 1H), 6.94 (s, 1H), 6.66 (s, 1H), 3.79 (s, 2H), 3.00-2.93 (m, 2H), 2.91-2.85 (m, 2H), 2.83-2.67 (m, 4H), 2.29 (s, 3H), 1.96-1.84 (m, 2H).

TABLE 49 Examples in the following table were prepared using similar conditions as described in Example 669 and Scheme XII from appropriate starting materials. Exact Example Mass # Cmpd # Structure IUPAC Name [M + H]⁺ 672 910

N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-4- ((methylamino)methyl)thiophene- 2-sulfonimidamide 405

Example 673 (Compound 922a)

2-((R)-1-amino-2-hydroxypropan-2-yl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiazole-5-sulfonimidamide (Scheme XIII)

To a stirred solution of 2-((R)-1-azido-2-hydroxypropan-2-yl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)thiazole-5-sulfonimidamide (100 mg, 0.22 mmol) in THF (10 mL) in a 50-mL round-bottom flask under nitrogen was added LiAlH₄ (17 mg, 0.44 mmol) at 0° C. The resulting solution was stirred for 2 h at 0° C. The reaction was quenched with water/ice at 0° C. The resulting mixture was filtered. The filter cake was washed with water (3×5 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Sunfire prep C18 column, 30*150, 5 um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 37% B over 7 min; Rt₁: 4.72, UV 254/210 nm. This resulted in 8.2 mg (8.7%) of Example 673 as a white solid. MS-ESI: 436 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ: 8.46 (br, s, 1H), 8.18 (s, 1H), 7.17 (br, s, 4H), 6.89 (s, 1H), 3.10-2.98 (m, 2H), 2.84-2.74 (m, 4H), 2.73-2.61 (m, 4H), 2.00-1.87 (m, 4H), 1.53 (s, 3H).

Example 674 (Compound 896)

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((R)-5-methyl-2-oxooxazolidin-5-yl)thiazole-5-sulfonimidamide (Scheme XIV)

To a stirred solution of 2-((R)-1-amino-2-hydroxypropan-2-yl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)thiazole-5-sulfonimidamide (Ex. 673, 80 mg, 0.18 mmol) in THF (10 mL) in a 50-mL round-bottom flask under nitrogen was added bis(trichloromethyl) carbonate (23 mg, 0.09 mmol) at 0° C. The resulting mixture was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep C18 OBD Column, 19×150 mm 5 um; Mobile Phase A: Water (10 mM NH₄HCO₃+0.1% NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 13% B to 36% B over 7 min; Rt₁: 6.47, UV 254/210 nm. This resulted in 3.7 mg (4.4%) of Example 674 as a white solid. MS-ESI: 462 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (br s, 1H), 8.20 (s, 1H), 7.96 (s, 1H), 7.86 (br s, 2H), 6.88 (s, 1H), 3.79-3.71 (m, 2H), 2.83-2.74 (m, 4H), 2.72-2.60 (m, 4H), 1.99-1.87 (m, 4H), 1.79 (s, 3H).

Example 675 (Compound 894)

N-((2R)-2-(5-(N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)thiazol-2-yl)-2-hydroxypropyl)acetamide (Scheme XV)

To a stirred solution of 2-((R)-1-amino-2-hydroxypropan-2-yl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)thiazole-5-sulfonimidamide (100 mg, 0.23 mmol) in DCM (10 mL) in a 50-mL round-bottom flask under nitrogen was added TEA (70 mg, 0.69 mmol) at RT, followed by the addition of Ac₂O (23 mg, 0.23 mmol) dropwise at 0° C. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep C18 OBD Column, 19×150 mm 5 um; Mobile Phase A: Water (10 mM NH₄HCO₃+0.1% NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 12% B to 20% B over 10 min; Rt₁: 12.43 min, Detector, UV 254/210 nm. This resulted in 5.3 mg (4.83%) of Example 675 as a white solid. MS-ESI: 478 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.41 (br, s, 1H), 8.08 (s, 1H), 7.98 (br s, 1H), 7.82 (br, s, 2H), 6.88 (s, 1H), 6.52 (s, 1H), 3.60-3.47 (m, 1H), 3.31-3.25 (m, 1H), 2.85-2.73 (m, 4H), 2.72-2.60 (m, 4H), 2.00-1.87 (m, 4H), 1.83 (s, 3H), 1.45 (s, 3H).

Example 676 (Compound 894a)

Tert-butyl ((2R)-2-(5-(N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)thiazol-2-yl)-2-hydroxypropyl)carbamate (Scheme XVI)

To a stirred solution of 2-((R)-1-amino-2-hydroxypropan-2-yl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)thiazole-5-sulfonimidamide (100 mg, 0.23 mmol) in DCM (10 mL) in a 50-mL round-bottom flask was added TEA (70 mg, 0.69 mmol) at RT, followed by the addition of Boc₂O (50 mg, 0.23 mmol) in THF (5 mL) dropwise at 0° C. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5 um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 45% B to 70% B over 7 min; Rt₁: 6.28 min, UV 254/210 nm. This resulted in 5.5 mg (4.47%) of Example 676 as a white solid. MS-ESI: 536 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (br, s, 1H), 8.08 (s, 1H), 7.87 (br, s, 2H), 6.88 (s, 1H), 6.73 (br s, 1H), 6.33 (s, 1H), 3.45-3.34 (m, 1H), 3.25-3.15 (m, 1H), 2.84-2.75 (m, 4H), 2.72-2.61 (m, 4H), 1.99-1.87 (m, 4H), 1.44 (s, 3H), 1.37 (s, 9H).

Example 677 (Compound 918a)

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((R)-2-hydroxy-1-(2-hydroxyethoxy)propan-2-yl)thiazole-5-sulfonimidamide (Scheme XVII)

To a stirred solution of 2-((R)-1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiazole-5-sulfonimidamide (80 mg, 0.14 mmol) in DCM (3.0 mL) in a 50-mL round-bottom flask under nitrogen was added trichloroborane (0.50 mL) dropwise at 0° C. The resulting mixture was stirred for 16 h at RT. The reaction was quenched with water at 0° C. The resulting mixture was extracted with DCM (3×30 mL). The combined organic layers were washed with brine (1×30 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: XBridge Prep C18 OBD Column, 19×150 mm 5 um; Mobile Phase A: Water(10 mM NH₄HCO₃+0.1% NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient:8 B to 38 B over 7 min; Rt₁: 5.50; Detector, UV 254/210 nm. This resulted in 33.3 mg (49%) of Example 677 as a white solid. MS-ESI: 480 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (br s, 1H), 8.08 (s, 1H), 7.85 (br s, 2H), 6.88 (s, 1H), 6.28 (s, 1H), 4.58 (br s, 1H), 3.69-3.58 (m, 2H), 3.61-3.44 (m, 4H), 2.84-2.75 (m, 4H), 2.72-2.61 (m, 4H), 1.99-1.87 (m, 4H), 1.47 (s, 3H).

TABLE 50 Examples in the following table were prepared using similar conditions as described in Example 451 and Scheme III from appropriate starting materials. Exact Example Mass # Cmpd # Structure IUPAC Name [M + H]⁺ 678 905

N′-((8-cyano-1,2,3,5,6,7- hexahydro-s-indacen- 4-yl)carbamoyl)-2- (1,2,3-trihydroxypropan- 2-yl)thiazole-5- sulfonimidamide 478

TABLE 51 Examples in the following table were prepared using similar conditions as described in Example 453 and Scheme IV from appropriate starting materials. Exact Example Mass # Cmpd # Structure IUPAC Name [M + H]⁺ 679 915

N′-((8-cyano-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)-4- (methoxymethyl)thiazole- 5-sulfonimidamide 490 680 912

5-(2-Hydroxypropan-2- yl)-N′-((1-oxo-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)thiazole-2- sulfonimidamide 435 681 906

N′-((8-cyano-1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)-4-(2- hydroxypropan-2-yl)pyridine-2- sulfonimidamide 440 682 897

N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-5- (2-hydroxypropan-2-yl)-1- (4-methoxybenzyl)-1H- pyrazole-3-sulfonimidamide 524 683 923a

2-((R)-1-(2-(benzyloxy)ethoxy)- 2-hydroxypropan-2-yl)- N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)thiazole- 5-sulfonimidamide 571 684 924a

N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-2- ((R)-2-hydroxy-1- (2-methoxyethoxy)propan-2- yl)thiazole-5-sulfonimidamide 495

TABLE 52 Examples in the following table were obtained from chiral HPLC resolutions of racemic examples described above. The chiral column and eluents are listed in the table. As a convention, the faster-eluting enantiomer is always listed first in the table followed by the slower-eluting enantiomer of the pair. The symbol * at a chiral center denotes that this chiral center has been resolved and the absolute stereochemistry at that center has not been determined. Assigned stereochemistry in compound names are tentative. Ex. Cmpd LC-MS # # Structure IUPAC Name Column Eluents [M + H]⁺ 685 912b

(R) or (S)-N′-((6- cyclopropyl-5-methyl- 2,3-dihydro- 1H-inden-4-yl) carbamoyl)-3- fluoro-5-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide CHIRALPAK IF, 2*25 cm, 5 um 20% EtOH in Hex (0.1% FA) 452 686 912a

(S) or (R)-N′-((6- cyclopropyl-5-methyl- 2,3-dihydro- 1H-inden-4-yl) carbamoyl)-3- fluoro-5-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide CHIRALPAK IF, 2*25 cm, 5 um 20% EtOH in Hex (0.1% FA) 452 687 906b

(R) or (S)- N′-((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl)-5- methyl-4,5,6,7- tetrahydrothieno [3,2-c]pyridine-2- sulfonimidamide CHIRALPAK ID, 2.0 cm I.D*25 cm L(5 um) 20% EtOH in Hex:DCM (3:1, 10 mM NH₃—MeOH) 431 688 906a

(S) or (R)- N′-((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl)-5- methyl-4,5,6,7- tetrahydrothieno [3,2-c]pyridine-2- sulfonimidamide CHIRALPAK ID, 2.0*25 cm L(5 um) 20% EtOH in Hex:DCM (3:1, 10 mM NH₃—MeOH) 431 691 910b

(R) or (S)- N′-((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl)-4- ((methylamino) methyl)thiophene- 2-sulfonimidamide CHIRALPAK ID, 2*25 cm (5 um) 30% EtOH in Hex:DCM (3:1, 10 mM NH₃—MeOH) 405 692 910a

(S) or (R)- N′-((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl)-4- ((methylamino) methyl)thiophene- 2-sulfonimidamide CHIRALPAK ID, 2*25 cm (5 um) 30% EtOH in Hex:DCM (3:1, 10 mM NH₃—MeOH) 405 693 897a

(R) or (S)- N′-((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl)- 4,7-dihydro-5H- thieno[2,3-c]pyran-2- sulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um 50% EtOH in Hex (0.1% FA) 418 694 897b

(S) or (R)- N′-((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl)- 4,7-dihydro-5H- thieno[2,3-c]pyran-2- sulfonimidamide CHIRALPAK IG, 20*250 mm, 5 um 50% EtOH in Hex (0.1% FA) 418 695 872c

(R) or (S)-(6R)- N′-((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl)-6- methoxy-6,7- dihydro-5H- pyrazolo[5,1- b][1,3]oxazine- 3-sulfonimidamide CHIRALPAK IC, 3*25 cm, 5 um 30% EtOH in Hex (8 mM NH₃•MeOH) 432 696 872b

(S) or (R)-(6R)- N′-((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl)-6- methoxy-6,7- dihydro-5H- pyrazolo[5,1- b][1,3]oxazine- 3-sulfonimidamide CHIRALPAK IC, 3*25 cm, 5 um 30% EtOH in Hex (8 mM NH₃•MeOH) 432 697 870c

(R) or (S)-(6R)- N′-((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl)-6- (methylamino)-6,7- dihydro-5H- pyrazolo[5,1- b][1,3]oxazine- 3-sulfonimidamide CHIRALPAK ID, 2*25 cm (5 um) 20% EtOH in Hex:DCM (3:1, 10 mM NH₃—MeOH) 431 698 870b

(S) or (R)-(6R)- N′-((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl)-6- (methylamino)-6,7- dihydro-5H- pyrazolo[5,1- b][1,3]oxazine- 3-sulfonimidamide CHIRALPAK ID, 2*25 cm (5 um) 20% EtOH in Hex:DCM (3:1, 10 mM NH₃—MeOH) 431

General Procedure for Reductive Amination

In a flame-dried 25 mL round bottom flask, a primary or secondary amine (0.41 mmol) and sodium triacetoxyborohydride (75 mg, 0.354 mmol) were added to a solution of tert-butyl (R)-((4-formylphenyl)(3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(oxo)-λ⁶-sulfanylidene)carbamate (100 mg, 0.207 mmol) in dry DCE (6 mL) under an argon atmosphere. The flask was sealed and the resulting cloudy mixture was stirred at RT for 18 h.

In cases where the reduction rate was extremely slow, additional portion of NaBH₄ (15 mg, 0.41 mmol) was added to the reaction flask and the resulting mixture was stirred at RT for additional 24 h.

The reaction was quenched with NaHCO₃ sat. solution (2.5 mL) and the product was extracted with EtOAc (3×10 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure at 30° C., to give the products as pale yellow solids.

General Procedure for Boc-Deprotection

In a 20 mL vial, the product of reductive amination (0.156 mmol) was dissolved in formic acid (0.9 mL) and the resulting solution was stirred at room temperature overnight (16 h). The solution was concentrated in vacuo at room temperature affording a pale yellow oil, which was triturated in EtOAc resulting in the formation of a white solid. The product was purified by reverse phase flash chromatography using a gradient of 70-100% CH₃CN in H₂O (formic acid 0.1%) generating the desired products as a white powders. Compounds were isolated as formate salts except where indicated.

Examples below were prepared from tert-butyl (R)-((4-formylphenyl)(3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(oxo)-λ⁶-sulfanylidene)carbamate following the general procedures for reductive amination and then Boc-deprotection above.

Example 699 (R)-4-((allylamino)methyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-benzenesulfonimidamide Example 700 (R)-4-((ethylamino)methyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-benzenesulfonimidamide Example 701 (R)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(((2-methoxyethyl)amino)-methyl)benzenesulfonimidamide Example 702 (R)-4-((sec-butylamino)methyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-benzenesulfonimidamide Example 703 (R)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(((tetrahydro-2H-pyran-4-yl)-amino)methyl)benzenesulfonimidamide Example 704 (R)-4-((cycloheptylamino)methyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-carbamoyl)-benzenesulfonimidamide Example 705 (R)-4-((cyclobutylamino)methyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-benzenesulfonimidamide Example 706 (R)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-((isopropylamino)methyl)-benzenesulfonimidamide Example 707 (R)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-((4-methylpiperazin-1-yl)-methyl)benzenesulfonimidamide Example 708 (R)-4-(((2,2-difluoroethyl)amino)methyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-carbamoyl)benzenesulfonimidamide Example 709 (R)-4-((cyclobutyl(methyl)amino)methyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-carbamoyl)benzenesulfonimidamide

TABLE 53 Structure and analytical data for Examples 699 to 709 Example Cmpd # Structure ¹H-NMR (400 MHz, CD₃OD) δ: ppm MS-ESI 699 885a

8.48 (br s, 1H), 8.04 ( br s, 2H), 7.64 (d, J = 8.2 Hz, 2H), 6.90 (s, 1H), 6.01-5.90 (m, 1H), 5.50-5.42 (m, 2H), 4.18 (s, 2H), 3.60 (d, J = 6.7 Hz, 2H), 2.84-2.81 (m, 4H), 2.78- 2.67 (m, 4H), 2.04-1.97 (m, 4H). 425.3 700 884a

8.53 ( br s, 1H), 8.04 ( br s, 2H), 7.64 (d, J = 8.1 Hz, 2H), 6.90 (s, 1H), 4.61 ( br s, 2H), 4.18 (s, 2H), 3.02 (q, J = 7.3 Hz, 2H), 2.84-2.80 (m, 4H), 2.78-2.68 (m, 4H), 2.04- 1.97 (m, 4H), 1.29 (t, J = 7.3 Hz, 3H). 413.3 701 883a

8.02 ( br s, 2H), 7.63 (d, J = 8.1 Hz, 2H), 6.90 (s, 1H), 4.61 ( br s, 3H), 4.16 (s, 2H), 3.62-3.59 (m, 2H), 3.39 (s, 3H), 3.09-3.06 (m, 2H), 2.84-2.80 (m, 4H), 2.76-2.69 (m, 4H), 2.04-1.96 (m, 4H). 443.3 702 882a

8.51 (s, 1H), 8.05 ( br s, 2H), 7.67 (d, J = 8.2 Hz, 2H), 6.90 (s, 1H), 4.62 ( br s, 2H), 4.29 (d, J = 13.4 Hz, 1H, AB system), 4.23 (d, J = 13.4 Hz, 1H, AB system), 3.22-3.13 (m, 1H), 2.84-2.80 (m, 4H), 2.78-2.69 (m, 4H), 2.04- 1.97 (m, 4H), 1.94-1.84 (m, 1 H), 1.63-1.51 (m, 1H), 1.35 (d, J = 6.6 Hz, 3H), 1.02 (t, J = 7.5 Hz, 3H). 441.3 703 880a

8.43 (s, 1H), 8.05 ( br s, 2H), 7.67 (d, J = 8.1 Hz, 2H), 6.90 (s, 1H), 4.26 (s, 2H), 4.03 (dd, J = 11.8, 4.4 Hz, 2H), 3.43 (t, J = 11.8 Hz, 2H), 3.38- 3.33 (m, 1H), 2.84-2.81 (m, 4H), 2.78-2.69 (m, 4H), 2.08-1.96 (m, 6H), 1.67 (qd, J = 12.1, 4.6 Hz, 2H). 469.4 704 879a

8.51 (s, 1H), 8.04 ( br s, 2H), 7.66 (d, J = 8.2 Hz, 2H), 6.90 (s, 1H), 4.60 ( br s, 3H), 4.25 (s, 2H), 3.27-3.19 (m, 1H), 2.84-2.80 (m, 4H), 2.78- 2.68 (m, 4H), 2.18-2.11 (m, 2H), 2.04-1.97 (m, 4H), 1.85-1.77 (m, 2H), 1.72- 1.50 (m, 8H). 481.4 705 878a

8.48 (s, 1H), 8.04 ( br s, 2H), 7.64 (d, J = 8.2 Hz, 2H), 6.90 (s, 1H), 4.12 (s, 2H), 3.73 (quin, J = 8.1 Hz, 1H), 2.84-2.80 (m, 4H), 2.78- 2.68 (m, 4H), 2.34-2.28 (m, 2H), 2.21-2.11 (m, 2H), 2.04-1.97 (m, 4H), 1.93-1.84 (m, 2H). 439.3 706 877a

8.51 (s, 1H), 8.05 ( br s, 2H), 7.67 (d, J = 8.1 Hz, 2H), 6.90 (s, 1H), 4.25 (s, 2H), 3.40 (sep, J = 6.5 Hz, 1H), 2.84-2.80 (m, 4H), 2.77- 2.69 (m, 4H), 2.04-1.97 (m, 4H), 1.37 (d, J = 6.5 Hz, 6H). 427.3 707 876a

8.45 ( br s, 1H), 7.96 ( br s, 2H), 7.55 (d, J = 8.1 Hz, 2H), 6.90 (s, 1H), 3.68 (s, 2H), 3.08 ( br s, 4H), 2.84-2.80 (m, 4H), 2.77-2.62 (m, 8H), 2.71 (s, 3H), 2.03-1.96 (m, 4H). 468.4 708 881a

8.38 ( br s, 1H), 7.96 ( br s, 2H), 7.55 (d, J = 8.1 Hz, 2H), 6.89 (s, 1H), 5.91 (tt, J = 56.2, 4.2 Hz, 1H), 3.92 (s, 2H), 2.91 (td, J = 15.5, 4.2 Hz, 2H), 2.84-2.80 (m, 4H), 2.77- 2.68 (m, 4H), 2.04-1.96 (m, 4H). 449.3 709 827a

7.98 ( br s, 2H), 7.55 (d, J = 8.1 Hz, 2H), 6.89 (s, 1H), 3.66 (s, 2H), 3.14-3.06 (m, 1H), 2.84-2.80 (m, 4H), 2.76- 2.68 (m, 4H), 2.15 (s, 3H), 2.14-2.09 (m, 2H), 2.05-1.96 (m, 6H), 1.79-1.68 (m, 2H). 453.3

Examples 710 (Compound 875a) and 711 (Compound 875b)

(R)- and (S)-1-(Difluoromethyl)-4-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonimidamide

Step 1: 4-Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

In a 1-L flask, a cold (0° C.) solution of 4-fluoro-1H-pyrazole (14.14 g, 115.0 mmol) in dry DMF (150 mL) was treated carefully portion-wise with NaH (60% in oil, 5.31 g, 132.8 mmol) over 20 min. The suspension was then treated dropwise with SEM-Cl (23.0 mL, 129.7 mmol) keeping the internal temperature below 10° C. The suspension was left to warm to RT and stirred for 7 h. The reaction was diluted with EtOAc (500 mL) and quenched with half-saturated brine (1.4 L). The organic layer was separated and washed again with half-saturated brine (2×500 mL) and brine (300 mL). The aqueous phases were back extracted with EtOAc (2×500 mL). The organic layers were combined and dried over Na₂SO₄, filtered and concentrated in vacuo. Purification on normal phase silica using a gradient of 100% hexanes to 30% EtOAc/hexanes gave 23.0 g of the title compound as a colorless oil (85%). MS-ESI: 217.1 (M+1).

Step 2: lithium 4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-sulfinate

In a 1-L round bottom flask, a cold (-70° C.) solution of 4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (19.98 g, 92.36 mmol) in dry THF (150 mL) was treated dropwise with n-BuLi (2.5 M in hexanes, 40.0 mL, 100.00 mmol) over 20 min by the keeping internal temperature below −65° C. After 1 h at −70° C., an atmosphere of SO₂ (g) was introduced via balloon. After stirring for 20 min at −70° C. the dry-ice bath was removed, and the reaction mixture was left to warm to RT. The suspension was left to stir at RT for 30 min. The crude reaction mixture was concentrated in vacuo to provide a beige solid. The material was mixed with DCM (200 mL) and sonicated for 15 min and triturated over 5 h. The solid was collected by filtration and after drying under vacuum 24.39 g (86%) of the title compound was isolated as a beige solid. The product was used as is in the next step.

Step 3: N,N-dibenzyl-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-sulfonamide

In a 100-mL round bottom flask, a cold (0° C., ice-water bath) suspension of lithium 4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-sulfinate (24.4 g, 79.76 mmol) in a mixture of DCM (200 mL) and water (100 mL) was treated in two portions with NCS (11.98 g, 89.715 mmol) over 3-5 min under vigorous stirring by keeping internal temperature below 10° C. The biphasic solution was stirred for 1 h.

To the biphasic reaction mixture cooled at 0° C., Et₃N (15 mL, 107.6 mmol) was added in one portion followed by N,N-dibenzylamine (20.0 mL, 104.0 mmol). Internal temperature was kept below 7-8° C. Then, the ice-water bath was removed and the reaction was left to warm to RT over 1 h. The biphasic solution was diluted with more DCM (100 mL) and water (100 mL). The organic layer was separated and washed with water (100 mL) again. The aqueous layers were back extracted with DCM (2×100 mL). The organic layers were combined, cooled to 0° C., and treated slowly by the addition of aq. HCl 0.5 N (120 mL, 60 mmol) over 5-10 min by keeping internal temperature below 10° C. The organic layer was separated (500 mL) and washed with half-saturated brine (100 mL). The aqueous layers were back extracted with DCM (100 mL).

The organic layers were combined, dried over Na₂SO₄, concentrated and purified through the use of a short silica plug, eluting with dichloromethane. 31.88 g (80%) of the title compound was isolated as a colorless oil. MS-ESI: 498.2 (M+Na).

Step 4: N,N-dibenzyl-4-fluoro-1H-pyrazole-5-sulfonamide

In a 1000-ml round bottom flask, a cold (0° C.) solution of N,N-dibenzyl-4-fluoro-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-pyrazole-5-sulfonamide (31.76 g, 66.77 mmol) in DCM (100 mL) was treated slowly with TFA (50 mL, 653 mmol). The ice-water bath was removed and the reaction was left to warm to RT and stirred for 2 h. The reaction was concentrated in vacuo and the residue was dissolved in 1,4-dioxane (45 mL), cooled to 10° C., and treated very slowly over 5 min with conc. NH₄OH (28-30%, 45 mL, 335 mmol). The mixture was stirred for 2 h at RT. The reaction mixture was diluted with water (100 mL) and brine (100 mL) and extracted with EtOAc (200 mL). The organic layer was washed with brine (100 mL). The aqueous phases were back extracted with EtOAc (150 mL). The organic layers were combined, dried over Na₂SO₄, filtered and concentrated in vacuo.

After evaporation, a waxy gummy white solid was obtained. This crude material was purified by normal phase silica column chromatography, eluting with EtOAc/hexanes (1:2). The title compound was isolated as a white solid (17.62 g, 72%). MS-ESI: 346.1 (M+1).

Step 5: N,N-dibenzyl-1-(difluoromethyl)-4-fluoro-1H-pyrazole-3-sulfonamide

In a 1-L round bottom flask equipped with a condenser, a suspension of N,N-dibenzyl-4-fluoro-1H-pyrazole-5-sulfonamide (17.49 g, 50.638 mmol), sodium chlorodifluoroacetate (9.48 g, 62.18 mmol) and Cs₂CO₃ (20.07 g, 61.60 mmol) in anhydrous DMF (70 mL) was heated slowly to 130° C. over 2 h. The reaction was maintained at this temperature for 16 h. The brown suspension was cooled to RT and poured into half-saturated brine (700 mL) and extracted with EtOAc (250 mL). The organic layer was washed again with half-saturated brine (300 mL) and then brine (150 mL). The aqueous phases were back extracted with EtOAc (200 mL). The organic layers were combined and dried over Na₂SO₄. After concentration, the resulting dark residue was purified by silica column chromatography, eluting with EtOAc/hexanes (1:1). After evaporation, the title compound was isolated as a brown oil (15.12g, 65%). MS-ESI: 418.1 (M+1).

Step 6: 1-(difluoromethyl)-4-fluoro-1H-pyrazole-3-sulfonamide

In a 1-L round bottom flask (1000 mL), finely powdered N,N-dibenzyl-1-(difluoromethyl)-4-fluoro-1H-pyrazole-3-sulfonamide (15.1 g, 32.9 mmol) was cooled to 0° C., treated with cold conc. H₂SO₄ (90 mL, 1620 mmol) and stirred at 0° C. for 60 min. The yellow suspension was added dropwise to ice and the suspension was diluted with water (1.5 L) and solid NaCl (200 g) was added. The aqueous phase was extracted with EtOAc (800 mL) and washed with brine (200 mL). The aqueous phases were back extracted with EtOAc (2×400 mL). The organic layers were combined, dried over Na₂SO₄, filtered through Celite and concentrated in vacuo. The residue was re-dissolved in EtOAc (200 mL) and decolorized using active charcoal. The solution was concentrated in vacuo. The crude was triturated with DCM (100 mL) and heptane (150 mL). After filtration and drying, the title compound was isolated (4.807 g, 66%) as a beige solid. MS-ESI: 216.1 (M+1).

Step 7: N-(tert-butyldimethylsilyl)-1-(difluoromethyl)-4-fluoro-1H-pyrazole-3-sulfonamide

In a 100-mL round bottom flask, a cold (0° C.) solution of 1-(difluoromethyl)-4-fluoro-1H-pyrazole-3-sulfonamide (1.015 g, 4.716 mmol) in THF (4 mL) was treated dropwise with Et₃N (1.4 mL, 10 mmol) keeping internal temperature below 5° C. After 5 min, a solution of tert-butyldimethylsilyl chloride (975 mg, 6.469 mmol) in toluene (0.9 mL) was added via a cannula by keeping internal temperature below 7° C. The suspension was warmed to RT and heated to 70° C. for 3 h.

The reaction mixture was diluted with MTBE (50 mL). The organic phase was washed twice with aq. NaHCO₃ (2×40 mL), and brine (40 mL). The organic phase was dried over Na₂SO₄, treated with active charcoal (160 mg), filtered through Celite and concentrated in vacuo. The residue was co-evaporated with heptane. The solid obtained was triturated with heptane (45 mL) and MTBE (3 mL) overnight. After filtration and drying, the title compound was isolated as a beige solid (1.07 g, 67%). MS-ESI: 330.1 (M+1).

Step 8: (R)-1-(difluoromethyl)-4-fluoro-N-((S)-1-(4-methoxyphenyl)ethyl)-1H-pyrazole-3-sulfonimidamide and (S)-1-(difluoromethyl)-4-fluoro-N-((S)-1-(4-methoxyphenyl)ethyl)-1H-pyrazole-3-sulfonimidamide (D-8A and D-8B)

In a 25-mL round bottom flask, a cold (0° C.) solution of PPh₃Cl₂ (826 mg, 2.48 mmol) in dry DCM (4 mL) was treated dropwise with Et₃N (0.52 mL, 3.73 mmol). The ice water bath was removed and a suspension was obtained. The reaction was allowed to warm to RT and stirred for 10 min at this temperature. The white suspension was cooled to −70° C. and a solution of N-(tert-butyldimethylsilyl)-1-(difluoromethyl)-4-fluoro-1H-pyrazole-3-sulfonamide (405 mg, 1.23 mmol) in DCM (2 mL) was added via a cannula by keeping internal temperature below −50° C. The dry ice bath was removed and the reaction was allowed to warm to 0° C. The reaction was stirred at 0° C. for 30 min. Then, the reaction mixture was cooled back to −70° C. and (S)-(−)-4-Methoxy-α-methylbenzylamine (0.55 mL, 3.72 mmol) was added dropwise by keeping internal temperature below −45° C. After 5 min, the dry ice bath was removed and the suspension was left to warm to 0° C. The suspension was stirred at 0° C. for 30 min and left to warm to RT for an additional stirring period of 90 min.

The solvent was removed under reduced pressure to give a crude residue which was treated with a mixture of ACN (4 mL), water (2 mL) and HCOOH (0.46 mL, 12.2 mmol). The reaction was stirred at RT for 2 h. The reaction was concentrated under vacuum to remove half the volume of ACN and, after, diluted with EtOAc (50 mL), washed with 1% HCOOH in half-saturated brine (2×30 mL), aq. NaHCO_(3:)brine (1:1) (2×30 mL) and brine (25 mL). The aqueous phases were back extracted with EtOAc (50 mL). The organic layers were combined and dried over Na₂SO₄, filtered and concentrated in vacuo. The crude residue was dissolved in DCM/hexanes (1:1) and purified on silica gel column by eluting with a gradient of 100% hexanes to 90% EtOAc/hexanes. The title compounds were isolated as white solids (first eluting diastereomer D-8A, R_(f)=0.60 (DCM/EtOAc=1:1), 104.9 mg, 24% yield, and second eluting diastereomer D-8B, R_(f)=0.51 (DCM/EtOAc=1:1), 73 mg, 17% yield). Absolute stereochemistry was not determined. MS-ESI: 371.1 (M+Na).

Step 9: (R)-1-(difluoromethyl)-4-fluoro-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N-((S)-1-(4-methoxyphenyl)ethyl)-1H-pyrazole-3-sulfonimidamide and (S)-1-(difluoromethyl)-4-fluoro-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N-((S)-1-(4-methoxyphenyl)ethyl)-1H-pyrazole-3-sulfonimidamide (I-9A and I-9B)

In a 25 mL round bottom flask, a solution of 1-(difluoromethyl)-4-fluoro-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N-((S)-1-(4-methoxyphenyl)ethyl)-1H-pyrazole-3-sulfonimidamide (diastereomer D-8A, 49.4 mg, 0.142 mmol) in EtOAc (1.5 mL) was treated with 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (33.5 mg, 0.168 mmol) in one portion. The reaction was stirred for 1 h at RT. Then, heptane (2 mL) was added dropwise over 2-3 min and a white solid was observed. The mixture was stirred at RT for a total of 2 h. The white solid was collected by filtration and the material was washed with EtOAc/heptane (1 mL/2 mL) and dried under high vacuum to give the title compound as diastereomer D-9A (43.4 mg, 55%) as a white solid. Similarly, 40 mg of Diastereomer B gave diastereomer D-9B (43.9 mg, 69%). MS-ESI: 548.2 (M+1).

Step 10: (S)-1-(difluoromethyl)-4-fluoro-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonimidamide and (R)-1-(difluoromethyl)-4-fluoro-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-carbamoyl)-1H-pyrazole-3-sulfonimidamide (Examples 710 and 711)

In a 5-mL round bottom flask, a cold (0° C.) suspension of diastereomer D9-A (31.4 mg, 0.057 mmol) in DCM (1 mL) was treated dropwise with TFA (0.4 mL, 5.2 mmol). The resulting solution was left to warm to RT by removing the ice-water bath after 5 min. The solution was stirred at RT for 2 h. Then, the reaction mixture was added to a 50 mL flask containing heptane (20 mL) and the solution was concentrated in vacuo. The material was suspended in DCM (20 mL) and heptane (20 mL) was added and triturated overnight at RT. The white solid was collected by filtration, washed with DCM/heptane (1:1, 2×2 mL) to afford 18.6 mg (76%) of the title product (Example 710). Absolute stereochemistry was not determined. ¹H NMR (400 MHz, DMSO): δ 8.62 (d; J=4.59 Hz; 1H); 8.45 (br s; 1H); 7.90 (s; 2H); 7.83 (t; J=58.27 Hz; 1H); 6.86 (s; 1H); 2.75 (t; J=7.35 Hz; 4H); 2.56-2.69 (m; 4H); 1.86-1.93 (m; 4H). MS(ESI): 414.1 (M+1).

Example 711 was generated from diastereomer D-9B using the same procedure, yielding 17.6 mg (73%) of product. Absolute stereochemistry was not determined. ¹H NMR (400 MHz, DMSO): δ 8.62 (d; J=4.57 Hz; 1H); 8.46 (br s; 1H); 7.90 (s; 2H); 7.83 (t; J=58.25 Hz; 1H); 6.85 (s; 1H); 2.75 (t; J=7.32 Hz; 4H); 2.54-2.68 (m; 4H); 1.86-1.93 (m; 4H). MS(ESI): 414.1 (M+1).

Example 712 (Compound 886a)

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)-N-((R)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide

Step 1: lithium 2-(5-sulfinatothiazol-2-yl)propan-2-yl sulfite

In a flame-dried 500 mL round bottom flask, a cold (-70° C.) solution of 2-(thiazol-2-yl)propan-2-ol (10.101 g, 70.538 mmol) in dry THF (100 mL) was treated dropwise with n-BuLi (2.5 M in hexanes, 60 mL, 150 mmol). After 1 h at −70° C., an atmosphere of SO₂ (g) was introduced for 15 min using a balloon. Then, while maintaining the SO₂ atmosphere, the dry-ice bath was removed and the suspension was allowed to warm to RT over 30 minutes. The suspension was cooled to 0° C. and collected by filtration and washed with Et₂O. The very fine off-white powder was dried under high vacuum to give 23.4 g (94%) of the title compound as an off-white powder. MS(ESI): 208.0 (M+1).

Step 2: 2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide

In a 100 mL round bottom flask immersed in a cool water bath, a suspension of hydroxylamine-O-sulfonic acid (18.64 g, 164.8 mmol) in water (50 mL) was treated with NaOAc (9.007 g, 109.8 mmol) followed by addition of lithium 2-(5-sulfinatothiazol-2-yl)propan-2-yl sulfite (15.10 g, 55.13 mmol). The white suspension was stirred at RT for 1 h. The reaction mixture was diluted with more water and extracted with EtOAc. The organic layer was separated and washed with water and brine. The aqueous phases (pH around 1-2) were back extracted with EtOAc. The organic layers were combined and dried over Na₂SO₄, filtered and concentrated in vacuo. The off-white solid was triturated in CHCl₃ (250 mL) for 1 h under reflux. The hot suspension was cooled to RT and the material was collected by filtration. The filtered material was dried under high vacuum to give the title compound as an off-white solid (9.11 g, 72%). MS(ESI): 223.0 (M+1).

Step 3: N-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide

In a 100-mL round-bottom flask, a cloudy solution of 2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide (8.110 g, 36.49 mmol) in THF (30 mL) was treated with Et₃N (11.5 mL, 82.5 mmol). The mixture was cooled to 0° C. and a solution of tert-butyldimethylsilyl chloride (7.55 g, 50.1 mmol) in toluene (10 mL) was added. The suspension was warmed to RT and heated to 70° C. for 3 h.

The reaction mixture was diluted with MTBE. The organic phase was washed twice with aq. NaHCO₃, and brine, dried over Na₂SO₄, filtered through Celite® and concentrated in vacuo. The beige solid was recrystallized by dissolving in MTBE (20-40 mL) and adding heptane (300 mL). After filtration and drying, the title compound was isolated as an off-white solid (11.35 g, 91%). MS(ESI): 337.1 (M+1).

Step 4: 2-(2-hydroxypropan-2-yl)-N-((R)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide

In a 10 mL round-bottom flask, a suspension of PPh₃Cl₂ (380 mg, 1.140 mmol) in dry CHCl₃ (2 mL) was treated with Et₃N (0.25 mL, 1.79 mmol). The mixture was stirred for 10 min at RT. The white suspension was cooled to 0° C. and a solution of N-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)-thiazole-5-sulfonamide (201 mg, 0.597 mmol) in CHCl₃ (1 mL) was added via a cannula; a yellow solution was immediately obtained. The reaction mixture was stirred for 20 min at 0° C. To the reaction mixture was added (R)-(+)-4-methoxy-α-methylbenzylamine (0.175 mL, 1.185 mmol) in one portion at 0° C. The mixture was stirred at 0° C. for 30 min and warmed slowly to RT for 3 h. After an additional 6 h of stirring at RT, extra (R)-(+)-4-Methoxy-α-methylbenzylamine (0.045 mL, 0.305 mmol) was added and stirring continued for another 16 hours.

The solvent was removed under reduced pressure to give a crude residue which was dissolved in ACN (2 mL). To the suspension was added water (1 mL) and HCOOH (0.225 mL, 5.96 mmol) and a yellow cloudy solution was obtained. The reaction was stirred at RT for 1 h. The reaction was diluted with EtOAc, washed with 1% HCOOH in half-saturated brine (2×50 mL), aq. NaHCO₃:brine (1:1) (2×50 mL) and brine. The aqueous phases were back extracted with EtOAc. The organic layers were combined and dried over Na₂SO₄. The title compound was isolated as a 1:1 mixture of diastereomers (212 mg, quantitative) and was brought to the next step as is. MS(ESI): 356.1 (M+1).

Step 5: N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)-N-((R)-1-(4-methoxyphenyl)ethyl)thiazole-5-sulfonimidamide (Example 712)

In a 25 mL round-bottom flask, a mixture of crude 2-(2-hydroxypropan-2-yl)-N-((R)-1-(4-methoxyphenyl)-ethyl)thiazole-5-sulfonimidamide (0.597 mmol) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (138 mg, 0.693 mmol) was dissolved in EtOAc (2 mL). The clear reaction solution was stirred at RT for 3 h. A white precipitate was observed to form after 30 min. The suspension was diluted with more EtOAc (4 mL) and collected by filtration. The white solid was washed with more EtOAc (3×), dried under high vacuum overnight giving 207 mg (61%) of the title compound as a white solid (1:1 mixture of diastereomers as measured by proton NMR). MS(ESI): 555.2 (M+1).

Example 713 (Compound 874b)

(R)-2-((S)-1,2-dihydroxypropan-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiazole-5-sulfonimidamide

Step 1: (S)-2-(thiazol-2-yl)propane-1,2-diol (E-1S)

In a 1 L round-bottom flask, t-BuOH (230 mL), water (230 mL) and THF (230 mL) was added, AD-mix-beta (111.8 g, 1.4 g per mmol of propenyl thiazole), followed by methanesulfonamide (7.60 g, 79.88 mmol) and (DHQD)₂AQN (2.74 g, 3.195 mmol). The reaction mixture was cooled to 0° C. with a mechanical stirrer. Into the cooled reaction mixture was added 2-propenyl thiazole (10 g, 79.8 mmol) and stirred for approximately 1 h at this temperature and then the ice-water bath was removed and stirred at RT for 24 h. The reaction mixture was diluted with H₂O (100 mL) and was extracted with EtOAc (3×400 mL). The combined organic extracts were washed with H₂O (75 mL) and brine (100 mL), dried over Na₂SO₄ and concentrated to give a yellowish orange solid. The crude material was purified by column chromatography using silica gel (20% methanol in DCM) to give 9.2 g of the product with 80% ee. Crystallization from mixture of ethyl acetate (140 mL), methanol (10 mL) and hexanes (420 mL) gave 6.4 g (70%) as a white solid with 99% ee. Chiral HPLC conditions; 70% hexanes +30% ethanol (0.1% DEA), Chiralpak IF column, flow rate; 1 mL/min, run time; 15 mins, R_(t)=10.3 min).

Step 2: (S)-2-(2,2,4-trimethyl-1,3-dioxolan-4-yl)thiazole (E-2S)

In a 25 mL single neck round bottom flask was charged (S)-2-(thiazol-2-yl)propane-1,2-diol (6.4 g, 40.2 mmol, ee 99%) followed by acetone (50 mL) and stirred to get a clear solution at RT. pTSA (690 mg, 4.02 mmol) was added and stirred for 20 h at 40° C. The reaction mixture then cooled to RT, diluted with ethyl acetate (150 mL) and washed with satd. NaHCO₃ solution (20 mL). The collected organic layer was washed with brine solution (50 mL), dried over anhydrous Na₂SO₄ and concentrated to give a crude oil. The crude oil was purified on silica gel by eluting from 100% hexanes to 20% ethyl acetate to the title compounds as a colorless oil (4.8 g, 60%). The material was used in the next step as is.

Step 3: (S)-2-((S)-2,2,4-trimethyl-1,3-dioxolan-4-yl)thiazole-5-sulfinamide (D-3S)

This step was performed using the procedure described in Scheme 103, Step 3 from 300 mg of (S)-2-(2,2,4-trimethyl-1,3-dioxolan-4-yl)thiazole from the Step above to yield the title compound as a white solid (130 mg, 33%). MS(ESI): 263.0 (M+1).

Step 4: tert-butyl ((S)-(2-((S)-2,2,4-trimethyl-1,3-dioxolan-4-yl)thiazol-5-yl)sulfinyl)-carbamate (D-4S)

This step was performed using the procedure described in Scheme 103, Step 4 from 100 mg of (S)-2-((S)-2,2,4-trimethyl-1,3-dioxolan-4-yl)thiazole-5-sulfinamide (D-3S) to yield the title compound as a colourless viscous oil (110 mg, 80%).

Step 5: tert-butyl ((S)-amino(oxo)(2-((S)-2,2,4-trimethyl-1,3-dioxolan-4-yl)thiazol-5-yl)-λ⁶-sulfaneylidene)carbamate (D-5S)

This step was performed using the procedure described in Scheme 103, Step 5 from 110 mg of tert-butyl ((S)-(2-((S)-2,2,4-trimethyl-1,3-dioxolan-4-yl)thiazol-5-yl)sulfinyl)-carbamate (D-4S) to yield the title compound as an off-white solid (63 mg, 60%). MS(ESI): 378.1 (M+1).

Step 6: tert-butyl ((R)-(3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(oxo)(2-((S)-2,2,4-trimethyl-1,3-dioxolan-4-yl)thiazol-5-yl)-λ⁶-sulfaneylidene)carbamate (D-6S)

In a 10 mL round bottom flask was charged tert-butyl ((S)-amino(oxo)(2-((S)-2,2,4-trimethyl-1,3-dioxolan-4-yl)thiazol-5-yl)-λ⁶-sulfaneylidene)carbamate (D-5S, 25 mg, 0.06 mmol) followed by THF (2.0 mL) and cooled to 0° C. with stirring. Charged 1 M potassium tert-butoxide solution in THF (0.070 mL) and reaction mixture was stirred for 30 min at 0° C. The solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (13.2 mg in 0.5 mL THF) was added at 0° C. and then stirred for approx. 1 hours at RT. The reaction mixture was quenched with 1 M formic acid in THF (0.070 mL) at 0° C. and then extracted with ethyl acetate (25 mL) and filtered through Celite. The filtrate was concentrated under reduced pressure to afford an off-white solid. The residue was purified by column chromatography using a gradient of 100% ethyl acetate to 1% methanol in ethyl acetate. The title compound (25 mg, 66%) was isolated as an off-white solid and used in the next step as is.

Step 7: (R)-2-((S)-1,2-dihydroxypropan-2-yl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-thiazole-5-sulfonimidamide (Example 713)

In a 10 mL round-bottom flask was charged tert-butyl ((R)-(3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(oxo)(2-((S)-2,2,4-trimethyl-1,3-dioxolan-4-yl)thiazol-5-yl)-λ⁶-sulfaneylidene)carbamate (D-6S, 25 mg, 0.043 mmol) followed by anhydrous DCM (3 mL) and the reaction suspension was cooled to 0°-5° C. under an argon atmosphere. TFA was slowly added (0.05 mL) and stirred for 1 hour at 0° C. Added more TFA (0.3 mL) and reaction was stirred for additional 3 hours. Added slowly another 0.45 mL of TFA in to the reaction mixture and stirred for additional 2.5 hours at 0° C. The reaction solution was concentrated under reduced pressure and repeatedly co-evaporated with acetonitrile (3×5 mL) and concentrated.

The residue was dissolved DMSO and purified by C18 RP-HPLC by eluting with 100% water (0.1% TFA) to 95% acetonitrile in water. After lyophilization, the title compound was isolated as a white solid (12 mg, 58%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.41 (br s, 1H), 8.04 (s, 1H), 7.82 (s, 2H), 6.86 (s, 1H), 6.12 (s, 1H), 5.00 (t, J=6.0 Hz, 1H), 3.53 (d, J=6.1 Hz, 2H), 2.76 (t, J=7.4 Hz, 4H), 2.66 (s, 4H), 1.92 (p, J=7.4 Hz, 4H), 1.43 (s, 3H). MS(ESI): 437.1 (M+1).

Example 714 (Compound 874a)

(R)-2-((R)-1,2-dihydroxypropan-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiazole-5-sulfonimidamide

This compound was prepared as illustrated in Example 713 Steps 1-7 with replacement of reagents AD-mix-beta and (DHQD)₂AQN in Step 1 with AD-mix-alpha and (DHQ)₂AQN. ¹H NMR (400 MHz, DMSO): δ 8.41 (br s, 1H), 8.05 (s, 1H), 7.82 (br s, 2H), 6.86 (s, 1H), 6.12 (s, 1H), 4.99 (t, J=6.08 Hz, 1H), 3.53 (d, J=6.07 Hz; 2H), 2.76 (t; J=7.39 Hz, 4H), 2.55-2.70 (m, 4H), 1.92 (p, J=7.35 Hz, 4H), 1.43 (s, 3H). MS(ESI): 437.1 (M+1).

Example 715

N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-sulfonimidamide (Scheme XVIII) Examples 716 and Example 717

(S)- and (R)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-sulfonimidamide

Step 1: Tert-butyl 2-(N-(tert-butyldimethylsilyl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl) carbamoyl)sulfamidimidoyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate

To a stirred solution of tert-butyl 2-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)-6,7-dihydrothieno[3,2-c] pyridine-5(4H)-carboxylate (200 mg, 0.46 mmol) in THF (6.0 mL) in a 50-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 37 mg, 0.93 mmol) in portions at 0° C. The reaction mixture was stirred for 10 min at RT. Then to this was added a mixture of 3-isocyanato-2,4,5,6-tetrahydro-1H-cyclobuta[f]indene (86 mg, 0.46 mmol) in THF (2.0 mL) dropwise with stirring at 0° C. The reaction mixture was stirred for 2 h at RT and then quenched with 1.0 mL of water. The resulting mixture was extracted with 3×25 mL of EtOAc and the organic layers were combined. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was eluted from silica gel with DCM/MeOH (10:1). This resulted in 130 mg (46%) of the title compound as a light yellow solid. MS-ESI: 617 (M+1).

Step 2: N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine-2-sulfonimidamide

A solution of tert-butyl 2-(N-(tert-butyldimethylsilyl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl) carbamoyl)sulfamidimidoyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (130 mg, 0.21 mmol) in HCl in dioxane (4 M, 8.0 mL) in a 25-mL round-bottom flask was stirred for 30 min at RT. The reaction mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC using the following conditions: XBridge Prep C18 OBD Column, 19×150 mm 5 um; Mobile Phase A: water (10 mM NH₄HCO₃+0.1% NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 19% B to 38% B over 7 min; UV 210/254 nm; Rt₁: 6.92 min. This resulted in 50 mg (59%) of Example 715 as a white solid. MS-ESI: 403 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (s, 1H), 7.31 (s, 1H), 6.66 (s, 1H), 3.72 (s, 2H), 3.10-2.99 (m, 2H), 2.99-2.91 (m, 2H), 2.91-2.79 (m, 2H), 2.85-2.66 (m, 6H), 1.96-1.86 (m, 2H).

Step 3: Chiral Separation

Example 715 (40 mg) was resolved by Prep-Chiral-HPLC with the following conditions: CHIRALPAK IG, 2*25 cm, 5 um; Mobile Phase A: CO₂, Mobile Phase B: MeOH:ACN=1:1 (2 mM NH₃-MeOH); Flow rate: 45 mL/min; Gradient: 50% B; UV 220 nm; Rt₁: 8.28 min. (Example 716); Rt₂: 11.31 min. (Example 717). This resulted in 12.8 mg (99.9% ee) of Example 716 followed by 14.8 mg (97.5% ee) of Example 717, both as a white solid.

Example 716 MS-ESI: 403 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.19 (s, 1H), 7.26 (s, 1H), 6.64 (s, 1H), 3.70 (s, 2H), 3.10-3.00 (m, 2H), 3.00-2.90 (m, 2H), 2.90-2.81 (m, 2H), 2.82-2.65 (m, 6H), 1.95-1.83 (m, 2H). Example 717 MS-ESI: 403 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (s, 1H), 7.24 (s, 1H), 6.63 (s, 1H), 3.69 (s, 2H), 3.13-3.00 (m, 2H), 3.00-2.90 (m, 2H), 2.90-2.81 (m, 2H), 2.82-2.65 (m, 6H), 1.95-1.84 (m, 2H).

TABLE 60 Examples in the following table were prepared using similar conditions as described in Example 715 and Scheme XVIII from appropriate starting materials. Exact Mass Example # Structure IUPAC Name [M + H]⁺ 718

5-(Azetidin-1-ylmethyl)-3-fluoro-N′- ((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3- yl)carbamoyl)thiophene-2- sulfonimidamide 435 719

5-(Cyclopropyl(methylamino)methyl)-N′- ((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3- yl)carbamoyl)thiophene-2- sulfonimidamide 431 720

5-((S) or (R)- cyclopropyl(methylamino)methyl)-N′- ((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3- yl)carbamoyl)thiophene-2- sulfonimidamide 431 721

5-((R) or (S)- cyclopropyl(methylamino)methyl)-N′- ((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3- yl)carbamoyl)thiophene-2- sulfonimidamide 431 722

4-((Methylamino)methyl)-N′-((2,4,5,6- tetrahydro-1H-cyclobuta[f]inden-3- yl)carbamoyl)thiophene-2- sulfonimidamide 391 723

5-(cyclopropyl(methylamino)methyl)-N′- ((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)thiophene-2- sulfonimidamide 445 724

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2- sulfonimidamide 417 725

4-(1-(cyclobutylamino)ethyl)-2-fluoro-N′- ((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3- yl)carbamoyl)benzenesulfonimidamide 457 726

5-((Cyclobutylamino)methyl)-3-fluoro-N′- ((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)thiophene-2- sulfonimidamide 463 727

4-((cyclobutyl(methyl)amino)methyl)-2- fluoro-N′-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3- yl)carbamoyl)benzenesulfonimidamide 457 728

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-5-(2- (hydroxymethyl)phenyl)thiophene-2- sulfonimidamide 468 729

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-5-(2- hydroxyphenyl)thiophene-2- sulfonimidamide 454 730

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-5-((S)-pyrrolidin-2- yl)thiophene-2-sulfonimidamide (made from chiral Intermediate 195F) 431 731

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-5-((R)-pyrrolidin-2- yl)thiophene-2-sulfonimidamide (made from chiral Intermediate 195S) 431 732

3-Fluoro-N′-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3-yl)carbamoyl)- 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- sulfonimidamide 421

Example 733

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(hydroxymethyl)-2-(1,2,3-trihydroxypropan-2-yl)thiazole-5-sulfonimidamide (Scheme XIX)

Step 1: N′-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazole-5-sulfonimidamide

To a stirred solution of N′-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(5-hydroxy -2,2-dimethyl-1,3-dioxan-5-yl)thiazole-5-sulfonimidamide (150 mg, 0.27 mmol) in THF (10 mL) in a 50-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral, 43.2 mg, 1.08 mmol) in portions at 0° C. The resulting solution was stirred for 10 min at RT. Then to the above mixture was added 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (81 mg, 0.41 mmol) at RT. The resulting mixture was stirred for 4 h at RT. The reaction mixture was quenched with 2.0 mL of H₂O. The mixture was concentrated under vacuum. The residue was purified by Prep-TLC (PE/EtOAc 1:1). This resulted in 110 mg (54%) of the title compound as an off-white solid. MS-ESI: 751 (M+1).

Step 2: N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(hydroxymethyl)-2-(1,2,3-trihydroxypropan-2-yl)thiazole-5-sulfonimidamide

To a stirred solution of N′-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-hexahydro-s-indacen-4-yl)carbamoyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazole-5-sulfonimidamide (110 mg, 0.15 mmol) in THF (12 mL) in a 50-mL round-bottom flask was added HCl in dioxane (4 M, 4 mL) dropwise at RT. The reaction solution was stirred for 2 h at RT. The reaction solution was concentrated under vacuum. The crude product was purified by Prep-HPLC using the following conditions: XBridge Prep OBD C18 Column, 30×150 mm 5 um; Mobile Phase A: water (10 mM NH₄HCO₃+0.1% NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 35% B over 7 min; UV 210/254 nm; Rt₁: 6.2 min. This resulted in 32 mg (46%) of Example 733 as a white solid. MS-ESI: 483 (M+1). ¹H NMR (400 MHz, MeOH-d₄) δ 6.92 (s, 1H), 5.01-4.90 (m, 2H), 3.92-3.81 (m, 4H), 2.91-2.70 (m, 8H), 2.09-1.98 (m, 4H).

TABLE 61 Examples in the following table were prepared using similar conditions as described in Example 733 and Scheme XIX from appropriate starting materials. Exact Mass Example # Structure IUPAC Name [M + H]⁺ 734

1-(Difluoromethyl)-4-fluoro-N′-((2,4,5,6- tetrahydro-1H-cyclobuta[f]inden-3- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide 400

Example 735

5-((Dimethylamino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiophene-2-sulfonimidamide (Scheme XX)

Step 1: N-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiophene-2-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)thiophene-2-sulfonimidamide (800 mg, 2.4 mmol) in THF (50 mL) in a 100-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 192 mg, 4.8 mmol) in portions at 0° C. The reaction mixture was stirred for 10 min at RT. Then to the reaction mixture was added 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (382 mg, 1.92 mmol) in portions at 0° C. The reaction mixture was stirred for 2 h at RT and then quenched with 5.0 mL of water. The mixture was extracted with 3×150 mL of EtOAc and the organic layers were combined. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. This resulted in 950 mg (crude) of the title compound as yellow oil which was used in the next step without further purification. MS-ESI: 533 (M-q).

Step 2: 5-((Dimethylamino)methyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiophene-2-sulfonimidamide

The crude product of N-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiophene-2-sulfonimidamide (950 mg, crude) was applied on Prep-TLC and using DCM/MeOH (10:1) to keep Rf=0.4˜0.5, then left the product on TLC overnight at RT. The TBS group was removed on TLC to give the final product which was then eluted from TLC with DCM/MeOH (10:1). The final product was further purified by Prep-HPLC using the following conditions: XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; Mobile Phase A: water (10 mM NH₄HCO₃+0.1% NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 38 B to 50 B over 7 min; UV 210/254 nm; Rt: 5.53 min. This resulted in 280 mg (28%, over two steps) of Example 735 as a white solid. MS-ESI: 419 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (br s, 1H), 7.82 (br s, 2H), 7.63 (d, J=3.6 Hz, 1H), 7.49 (d, J=4.0 Hz, 1H), 6.88 (s, 1H), 4.73 (s, 2H), 2.89-2.72 (m, 4H), 2.82 (s, 6H), 2.71-2.61 (m, 4H), 1.98-1.87 (m, 4H).

TABLE 62 Examples in the following table were prepared using similar conditions as described in Example 735 and Scheme XX from appropriate starting materials. Exact Mass Example # Structure IUPAC Name [M + H]⁺ 736

1-Ethyl-N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide 374 737

1-Ethyl-N′-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide 360

Example 738

4-(Hydroxymethyl)-2-(2-hydroxypropan-2-yl)-N-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiazole-5-sulfonimidamide (Scheme XXI)

Step 1: N-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(2-hydroxypropan-2-yl)-N′-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiazole-5-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (200 mg, 0.42 mmol) in THF (20 mL) in a 100-mL round-bottom flask under nitrogen was added t-BuOK (94 mg, 0.83 mmol) in portions at 0° C. The reaction mixture was stirred for 10 min at RT. Then to the above mixture was added 2,2,2-trichloroethyl (3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamate (174 mg, 0.50 mmol) at RT. The reaction mixture was stirred for 4 h at RT. The reaction mixture was diluted with 20 mL of H₂O. The mixture was extracted with 3×30 mL of EtOAc and the organic layers were combined. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was purified by Prep-TLC with EtOAc/PE (1/1). This resulted in 239 mg (82%) of the title compound as a light yellow solid. MS-ESI: 693 (M+1).

Step 2: 4-(Hydroxymethyl)-2-(2-hydroxypropan-2-yl)-N′-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)thiazole-5-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(2-hydroxypropan-2-yl)-N′-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiazole-5-sulfonimidamide (20 mg, 0.029 mmol) in THF (5.0 mL) in a 25-mL round-bottom flask was added HF/Py (70% wt., 0.10 mL, 3.85 mmol). The reaction solution was stirred for 2 h at RT. The reaction solution was concentrated under vacuum. The crude product was purified by Prep-HPLC using the following conditions: XBridge Prep C18 OBD Column, 19*150 mm, 5 um; mobile phase, water (10 mL NH₄HCO₃+0.1% NH₃.H₂O) and ACN (5% Phase B up to 30% over 7 min). This resulted in 7.0 mg (52%) of Example 738 as a white solid. MS-ESI: 465 (M+1). ¹H NMR (300 MHz, MeOH-d₄) δ 7.13 (s, 1H), 4.99-4.86 (m, 2H), 3.07-2.99 (m, 2H), 2.96-2.87 (m, 2H), 2.84-2.74 (m, 2H), 2.71-2.63 (m, 2H), 2.08-1.93 (m, 2H), 1.58 (s, 6H).

TABLE 63 Examples in the following table were prepared using similar conditions as described in Example 738 and Scheme XXI from appropriate starting materials. Exact Mass Example # Structure IUPAC Name [M + H]⁺ 739

5-(Hydroxymethyl)-1-isopropyl-N′-((3- oxo-1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide 432

Example 740

5-(2-Hydroxypropan-2-yl)-1-isopropyl-N′-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonimidamide (Scheme XXII)

Step 1: N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-isopropyl-N′-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonimidamide

To a stirred solution of N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide (250 mg, 0.69 mmol) in THF (8.0 mL) in a 25-mL round-bottom flask under nitrogen were added DBU (233 mg, 1.53 mmol) and 2,2,2-trichloroethyl (3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamate (251 mg, 0.69 mmol) in portions at 0° C. in an ice/water bath. The reaction mixture was stirred overnight at RT. The reaction mixture was diluted with H₂O (8 mL). The mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (3×15 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted silica gel with PE/EtOAc (3:1). This resulted in 80 mg (20%) of the title compound as a yellow solid. MS-ESI: 574 (M+1).

Step 2: 5-(2-Hydroxypropan-2-yl)-1-isopropyl-N′-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)-1H-pyrazole-3-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-isopropyl-N′-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1H-pyrazole-3-sulfonimidamide (80 mg, 0.14 mmol) in THF (5.0 mL) was added HF-Pyridine (70% wt., 0.03 mL, 1.12 mmol) at RT. The reaction mixture was stirred for 2 h at RT. The pH value of the mixture was adjusted to pH 7 with sat. NaHCO₃ (aq.). The mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (5.0 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC using the following conditions: XBridge Prep OBD C18 Column, 30×150 mm, 5 um; Mobile Phase A: water (10 mM NH₄HCO₃+0.1% NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 45% B over 7 min; 254/210 nm; Rt₁: 6.43 min. This resulted in 25.6 mg (40%) of Example 740 as a white solid. MS-ESI: 399 (M+1). ¹H NMR (400 MHz, MeOH-d₄) δ 7.12 (s, 1H), 6.60 (s, 1H), 5.36-5.28 (m, 1H), 3.05 (t, J=5.6 Hz, 2H), 2.94 (t, J=7.6 Hz, 2H), 2.90-2.80 (m, 2H), 2.77-2.66 (m, 2H), 2.08-2.02 (m, 2H), 1.62 (s, 6H), 1.50 (d, J=6.8 Hz, 3H), 1.47 (d, J=6.8 Hz, 3H).

Example 741

2-((S)-1,2-dihydroxypropan-2-yl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)thiazole-5-sulfonimidamide (Scheme XXIII)

Step 1: N-(tert-butyldimethylsilyl)-2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)thiazole-5-sulfonimidamide

To a stirred solution of N′-(tert-butyldimethylsilyl)-2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (500 mg, 1.07 mmol) in THF (10 mL) in a 50-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 87 mg, 2.15 mmol) in portions at 0° C. The reaction mixture was stirred for 10 min at RT. To the above mixture was added trichloromethyl (2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamate (359 mg, 1.07 mmol) in portions at 0° C. The reaction mixture was stirred for 2 h at RT. The reaction was quenched with 10 mL of water. The mixture was extracted with 3×20 mL of EtOAc. The organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (2:1). This resulted in 300 mg (43%) of the title compound as light brown oil. MS-ESI: 651 (M+1)

Step 2: 2-((S)-1,2-dihydroxypropan-2-yl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl) carbamoyl)thiazole-5-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-2-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N′-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)thiazole-5-sulfonimidamide (300 mg, 0.46 mmol) in THF (10 mL) in a 50-mL round-bottom flask was added TBAF (480 mg, 1.84 mmol) at RT. The reaction mixture was stirred for 2 h at RT. The reaction mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc (100%). The product was further purified by Flash-Prep-HPLC using the following conditions: XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; Mobile Phase A: water (10 mM NH₄HCO₃+0.1% NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 25% B to 42% B over 7 min; 254/210 nm; Rt₁: 5.32 min. This resulted in 130 mg (67%) of Example 741 as an off-white solid. MS-ESI: 423 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (br s, 1H), 8.11 (s, 1H), 7.90 (br s, 2H), 6.67 (s, 1H), 6.14 (s, 1H), 5.00 (t, J=6.0 Hz, 1H), 3.55 (d, J=6.0 Hz, 2H), 3.05-2.95 (m, 2H), 2.95-2.85 (m, 2H), 2.82-2.60 (m, 4H), 1.95-1.85 (m, 2H), 1.45 (s, 3H).

TABLE 64 Examples in the following table were prepared using similar conditions as described in Example 741 and Scheme XXIII from appropriate starting materials. Exact Mass Example # Structure IUPAC Name [M + H]⁺ 742

2-((R)-1,2-dihydroxypropan-2-yl)-N′- ((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3- yl)carbamoyl)thiazole-5-sulfonimidamide 423

Example 743

2-((R)-1,2-dihydroxypropan-2-yl)-N′-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiazole-5-sulfonimidamide (Scheme XXIV)

Step 1: N-(tert-butyldimethylsilyl)-2-((R)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N′-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiazole-5-sulfonimidamide

To a stirred solution of N′-(tert-butyldimethylsilyl)-2-((R)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (300 mg, 0.64 mmol) in THF (10 mL) in a 100-mL round-bottom flask under nitrogen was added t-BuOK (217 mg, 1.93 mmol) in portions at 0° C. The reaction mixture was stirred for 10 min at RT. To the reaction mixture was added trichloromethyl (3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamate (202 mg, 0.58 mmol) in portions at 0° C. The reaction mixture was stirred for 16 h at RT. The reaction mixture was quenched with H₂O (10 mL). The mixture was extracted with 5×20 mL of EtOAc and the organic layers were combined. The organic layer was dried with anhydrous Na₂SO₄ and concentrated under vacuum. This resulted in 400 mg (91%) of the title compound as a brown solid. MS-ESI: 679 (M+1).

Step 2: 2-((R)-1,2-dihydroxypropan-2-yl)-N′-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) thiazole-5-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-2-((R)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-N′-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiazole-5-sulfonimidamide (200 mg, 0.30 mmol) in THF (10 mL) in a 100-mL round-bottom flask was added TBAF (509 mg, 1.95 mmol) at RT. The reaction solution was stirred for 2 h at RT. The reaction mixture was diluted with H₂O (10 mL). The mixture was extracted with 5×20 mL of EtOAc and the organic layers were combined. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was eluted from silica gel with DCM:MeOH (20:1). The product was further purified by Prep-HPLC using the following conditions: XBridge Prep C18 OBD Column, 19×150 mm, 5 um; Mobile Phase A: water (10 mM NH₄HCO₃+0.1% NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 5% B to 30% B over 7 min; UV 254/210 nm; Rt₁: 5.78 min. This resulted in 80 mg (60%) of Example 743 as a white solid. MS-ESI: 451 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 9.01 (s, 1H), 8.07 (s, 1H), 7.65 (br s, 2H), 7.09 (s, 1H), 6.12 (s, 1H), 4.99 (br s, 1H), 3.54 (s, 2H), 2.96 (t, J=5.2 Hz, 2H), 2.87 (t, J=7.2 Hz, 2H), 2.83-2.61 (m, 4H), 1.99-1.93 (m, 2H), 1.44 (s, 3H).

TABLE 65 Examples in the following table were prepared using similar conditions as described in Example 743 and Scheme XXIV from appropriate starting materials. Exact Mass Example # Structure IUPAC Name [M + H]⁺ 744

2-((S)-1,2-dihydroxypropan-2-yl)-N′-((3- oxo-1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)thiazole-5-sulfonimidamide 451

Example 745

(S)-3-(5,5-difluoro-7,9-dimethyl-5H-5λ₄,6λ₄-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-3-yl)-N-(4-(N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)benzyl)-N-methylpropanamide (Scheme XXV)

Step 1: (S)-3-(5,5-difluoro-7,9-dimethyl-5H-5λ₄,6λ₄-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-3-yl)-N-(4-(N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)benzyl)-N-methylpropanamide

To a stirred solution of (S)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-((methylamino)methyl) benzenesulfonimidamide (12 mg, 0.030 mmol) in DMF (0.50 mL) in a 25-mL round-bottom flask were added 2,5-dioxopyrrolidin-1-yl 3-(5,5-difluoro-7,9-dimethyl-5H-5λ₄,6λ₄-dipyrrolo[1,2-c:2′,1′-f][1,3,2] diazaborinin-3-yl)propanoate (11 mg, 0.027 mmol) and TEA (6.09 mg, 0.060 mmol) at RT. The reaction solution was stirred for 25 h at RT. The solution was purified by Prep-HPLC using the following conditions: XBridge Prep OBD C18 Column, 19*250 mm, 5 um; mobile phase, water (10 mM NH₄HCO₃+0.1% NH₃.H₂O) and ACN (54% PhaseB up to 69% over 10 min); UV 254/210. This resulted in 5.8 mg (29%) of Example 745 as a red solid. MS-ESI: 673 (M+1). ¹H NMR (400 MHz, MeOH-d₄) δ 7.95 (d, J=8.1 Hz, 2H), 7.47-7.35 (m, 3H), 7.01-6.88 (m, 2H), 6.35-6.20 (m, 2H), 4.79-4.61 (m, 2H), 3.29-3.20 (m, 2H), 3.00 (s, 3H), 2.94-2.60 (m, 10H), 2.53 (s, 3H), 2.28 (s, 3H), 2.05-1.94 (m, 4H).

Example 746 and Example 747

(S) and (R)-5-((S)-1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiophene-2-sulfonimidamide (Scheme 2)

Step 1: 5-((S)4-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)-N-(tert-butyldimethylsilyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiophene-2-sulfonimidamide

To a stirred solution of 5-((S)-1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)-N′-(tert-butyldimethylsilyl) thiophene-2-sulfonimidamide (350 mg, 0.72 mmol) in THF (8 mL) in a 25-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 52 mg, 2.17 mmol) in portions 0° C. The reaction mixture was stirred for 10 min at RT. To above mixture was added 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (144 mg, 0.72 mmol) in portions at 0° C. The reaction mixture was stirred for 3 h at RT. The reaction was quenched with 10 mL of water/ice at 0° C. The mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (3×15 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 469 mg (crude) of the title compound as a light yellow solid. MS-ESI: 684 (M+1).

Step 2: (S) and (R)-5-((S)-1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiophene-2-sulfonimidamide

To a stirred solution of 5-((S)-1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)-N-(tert-butyldimethyl-silyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiophene-2-sulfonimidamide (50 mg, crude) in THF (5.0 mL) in a 25-mL round-bottom flask was added HF/Py (70% wt., 0.1 mL, 3.7 mmol). The reaction mixture was stirred for 1 h at RT. The reaction mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC using the following conditions: XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; Mobile Phase A: water (10 mM NH₄HCO₃+0.1% NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 30% B to 50% B over 7 min; UV, 210/254 nm; Rt₁: 6.37 min. This resulted in 10 mg (25%) of Example 746 and 10 mg (25%) of Example 747, both as a white solid. MS-ESI: 570 (M+1).

Example 746 ¹H NMR (400 MHz, MeOH-d₄) δ 7.77 (s, 1H), 7.65 (s, 1H), 7.37-7.25 (m, 5H), 6.92 (s, 1H), 4.54 (s, 2H), 3.67-3.49 (m, 6H), 2.91-2.79 (m, 8H), 2.10-1.98 (m, 4H), 1.52 (s, 3H).

Example 747 ¹H NMR (400 MHz, MeOH-d₄) δ 7.56 (d, J=3.6 Hz, 1H), 7.40-7.25 (m, 5H), 7.00 (d, J=4.0 Hz, 1H), 6.92 (s, 1H), 4.55 (s, 2H), 3.72-3.58 (m, 6H), 2.90-2.71 (m, 8H), 2.10-1.95 (m, 4H), 1.60 (s, 3H).

Example 748

(S)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-((S)-2-hydroxy-1-(2-hydroxyethoxy)propan-2-yl)thiophene-2-sulfonimidamide (Scheme XVII)

Step 1: (S)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-((S)-2-hydroxy-1-(2-hydroxyethoxy)propan-2-yl)thiophene-2-sulfonimidamide

To a stirred solution of (S)-5-((S)-1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiophene-2-sulfonimidamide (20 mg, 0.035 mmol) in DCM (10 mL) was added BCl₃ in DCM (1 M, 0.1 mL, 0.1 mmol) dropwise at 0° C. under nitrogen atmosphere. The reaction mixture was stirred for 5 h at 0° C. The reaction was quenched with water/ice at 0° C. The mixture was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (3×10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product (20 mg) was purified by Prep-HPLC using the following conditions: XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; Mobile Phase A: water (10 mM, NH₄HCO₃+0.1% NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 32% B to 40% B over 10 min; UV 210/254 nm; Rt₁: 10.63 min. This resulted in 1.7 mg (10%) of Example 748 as a white solid. MS-ESI: 480 (M+1). ¹H NMR (300 MHz, MeOH-d₄) δ 7.87 (s, 1H), 7.78 (s, 1H), 6.94 (s, 1H), 3.69-3.50 (m, 6H), 2.91-2.70 (m, 8H), 2.11-1.96 (m, 4H), 1.54 (s, 3H).

TABLE 66 Examples in the following table were prepared using similar conditions as described in Example 748 and Scheme XVII from Example 747 and Example 759. Exact Mass Example # Structure IUPAC Name [M + H]+ 749

(R)-N′-((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl)carbamoyl)-5-((S)-2-hydroxy-1-(2- hydroxyethoxy)propan-2-yl)thiophene-2- sulfonimidamide 480 750

2-((S)-1,14-dihydroxy-3,6,9,12- tetraoxapentadecan-14-yl)-N′- ((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)thiazole-5-sulfonimidamide 613 751

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-2-(2-hydroxy-1,3-bis(2- hydroxyethoxy)propan-2-yl)thiazole-5- sulfonimidamide 541

Example 752

6-(Dimethylamino)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-sulfonimidamide (Scheme XXVI)

Step 1: Tert-butyl (2-(N-(tert-butyldimethylsilyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-carbamoyl)sulfamidimidoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)(methyl)carbamate

To a stirred solution of tert-butyl (2-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)-4,5,6,7-tetrahydro-benzo[b]thiophen-6-yl)(methyl)carbamate (30 mg, 0.065 mmol) in THF (5 mL) under nitrogen was added NaH (60% wt dispersion in mineral oil, 5.24 mg, 0.131 mmol) in portions at 0° C. The resulting mixture was stirred for 10 min at 0° C., then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (20 mg, 0.098 mmol) was added in one portion at 0° C. The resulting solution was stirred for 16 h at RT, then quenched with 10 mL of water. The resulting solution was extracted with 3×50 mL of EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 40 mg (93.1%) of the title compound as a yellow solid. MS-ESI: 659 (M+1).

Step 2: 6-(Dimethylamino)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydro-benzo[b]thiophene-2-sulfonimidamide

To a stirred solution of tert-butyl (2-(N-(tert-butyldimethylsilyl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl)(methyl)carbamate (20 mg, 0.044 mmol) in THF (10 mL) under nitrogen was added LAH (8.4 mg, 0.22 mmol) in one portion at 0° C. The resulting mixture was stirred for 16 h at RT. The reaction mixture was quenched with water (1 mL) and diluted with EtOAc (50 mL). The solids were filtered out and the filtrate was concentrated under vacuum. The residue was purified by Prep-HPLC using the following conditions: XBridge Shield RP18 OBD Column, 30*150 mm, 5 um; Mobile Phase A: water (10 mM NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 55% B over 7 min; 254/220 nm. This resulted in 3.5 mg (25%) of Example 752 as white solid. MS-ESI: 459 (M+1).

TABLE 67 Examples in the following table were prepared using similar conditions as described in Example 1 and Scheme 1 from appropriate starting materials. Exact Mass Example # Structure IUPAC Name [M + H]⁺ 753

2-(1,2-Dihydroxypropan-2-yl)-N′- ((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-4-(hydroxymethyl)thiazole- 5-sulfonimidamide 467 754

2-((R)-1,2-dihydroxypropan-2-yl)-N′- ((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-4-(hydroxymethyl)thiazole- 5-sulfommidamide 467 755

2-((S)-1,2-dihydroxypropan-2-yl)-N′- ((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-4-(hydroxymethyl)thiazole- 5-sulfonimidamide 467 756

2-(1,3-Dihydroxy-2-methylpropan-2-yl)- N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)thiazole-5-sulfonimidamide 451 757

2-(1,2-Dihydroxypropan-2-yl)-4- (hydroxymethyl)-N′-((2,4,5,6-tetrahydro- 1H-cyclobuta[f]inden-3- yl)carbamoyl)thiazole-5-sulfonimidamide 453

TABLE 68 Examples in the following table were prepared using similar conditions as described in Example 4 and Scheme 2 from appropriate starting materials. Exact Mass Example # Structure IUPAC Name [M + H]⁺ 758

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-6,7-dihydro-4H-thieno[3,2- c]pyran-2-sulfonimidamide 418 759

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-5-phenylthiophene-2- sulfonimidamide 438 760

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-5-(2-hydroxypropan-2-yl)- 4-phenylthiophene-2-sulfonimidamide 496 761

N-((1,2,3,5,6,7-hexahvdro-s-indacen-4- yl)carbamoyl)-2-((S)-16-hydroxy-1- phenyl-2,5,8,11,14-pentaoxaheptadecan- 16-yl)thiazole-5-sulfonimidamide 703 762

1-(3-((Dimethylamino)methyl)phenyl)-N′- ((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)methanesulfonimidamide 426 763

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-6-(2-hydroxypropan-2- yl)pyridine-2-sulfonimidamide 415 764

4-(1-(Dimethylamino)-2-methylpropan-2- yl)-N′-((1,2,3,5,6,7-hexahydro-s-indacen- 4-yl)carbamoyl)benzenesulfonimidamide 455 765

3-Fluoro-N'-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-5- isopropylpyridine-2-sulfonimidamide 417 766

2-Fluoro-4-(1-methylpiperidin-3-yl)-N′- ((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3- yl)carbamoyl)benzenesulfonimidamide 457 767

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-4-(hydroxymethyl)-5-(2- hydroxypropan-2-yl)thiazole-2- sulfonimidamide 451 768

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-5,6-dimethyl-5,6-dihydro- 4H-thieno[3,4-c]pyrrole-1- sulfonimidamide 431 769

3-Fluoro-5-methyl-N′-((2,4,5,6- tetrahydro-1H-cyclobuta[f]inden-3- yl)carbamoyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2- sulfonimidamide 435 770

3-Fluoro-N′-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3-yl)caibamoyl)-6,7- dihydro-4H-thieno[3,2-c]pyran-2- sulfonimidamide 422

TABLE 69 Examples in the following table were prepared using similar conditions as described in Example 251 and Scheme 35 from appropriate starting materials. Exact Mass Example # Structure IUPAC Name [M + H]⁺ 771

(S)-3-(3-(but-3-yn-1-yl)- 3H-diazirin-3-yl)- N-(4-(N′-((1,2,3,5,6,7- hexahydro-s- indacen-4- yl)carbamoyl) sulfamidimidoyl)benzyl)-N- methylpropanamide 547

TABLE 70 Examples in the following table were prepared using similar conditions as described in Example 453 and Scheme IV from appropriate starting materials. Exact Mass Example # Structure IUPAC Name [M + H]⁺ 772

N′-((8-cyano-1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-2-(1-hydroxy-2- methylpropan-2-yl)thiazole-5- sulfonimidamide 460 773

5-(2,2-Difluoroethyl)-N′-((2,4,5,6- tetrahydro-1H-cyclobuta[f]inden-3- yl)carbamoyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2- sulfonimidamide 467

TABLE 71 Examples in the following table were prepared using similar conditions as described in Example 497 and Scheme VI from appropriate starting materials. Exact Mass Example # Structure IUPAC Name [M + H]⁺ 774

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-5-methoxy-4,5,6,7- tetrahydrobenzo[c]thiophene-1- sulfonimidamide 446 775

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-6-methoxy-4,5,6,7- tetrahydrobenzo[c]thiophene-1- sulfonimidamide 446

TABLE 72 Examples in the following table were prepared using similar conditions as described in Example 513 and Scheme XI from appropriate starting materials. Exact Mass Example # Structure IUPAC Name [M + H]⁺ 776

2-Fluoro-N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-4-(1- methylpyrrolidin-3- yl)benzenesulfonimidamide 457

TABLE 73 Examples in the following table were prepared using similar conditions as described in Example 446 and Scheme 3 from appropriate starting materials. Exact Mass Example # Structure IUPAC Name [M + H]+ 777

3-Fluoro-4-((methylamino)methyl)-N′- ((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3- yl)carbamoyl)thiophene-2- sulfonimidamide 409 778

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-6-(methylamino)-4,5,6,7- tetrahydrobenzo[b]thiophene-2- sulfonimidamide 445 779

3-Fluoro-N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-4- ((methylamino)methyl)thiophene-2- sulfonimidamide 423 780

N′-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-2-(7-hydroxy-1,13- diphenyl-2,5,9,12-tetraoxatridecan-7- yl)thiazole-5-sulfonimidamide 721 781

4-(Difluoromethyl)-N′-((2,4,5,6- tetrahydro-1H-cyclobuta[f]inden-3- yl)carbamoyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2- sulfonimidamide 453 782

(S) or (R) -4-(difluoromethyl)-N′- ((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3-yl)carbamoyl)- 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- sulfonimidamide Prepared from Intermediate 214F 453 783

(R) or (S) -4-(difluoromethyl)-N′- ((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3-yl)carbamoyl)- 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- sulfonimidamide Prepared from Intermediate 214S 453

TABLE 74 Examples in the following table were prepared using similar conditions as described in Example 451 and Scheme III from appropriate starting materials. Exact Mass Example # Structure IUPAC Name [M + H]⁺ 784

(R)-2-(2-hydroxypropan-2-yl)-N′-((5-(2- methoxypyridin-4-yl)-2,3-dihydro-1H- inden-4-yl)carbamoyl)thiazole-5- sulfonimidamide 488

TABLE 75 Examples in the following table were obtained from chiral HPLC resolutions of racemic examples described above. The chiral column and eluents are listed in the table. LC- MS Ex. [M + # Structure IUPAC Name Column Eluents H]⁺ 787

(R) or (S)-N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2- sulfonimidamide CHIRAL- PAK IG, 2*25 cm, 5 um 50% in MeOH (8 mM NH₃•MeOH) in CO₂ 417 788

(S) or (R)-N′-((1,2,3,5,6,7-hexahydro-5- indacen-4-yl)carbamoyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2- sulfonimidamide CHIRAL- PAK IG, 2*25 cm, 5 um 50% in MeOH (8 mM NH₃•MeOH) in CO₂ 417 789

(R) or (S)-N′-((1,2,3,5,6,7-hexahydro-5- indacen-4-yl)carbamoyl)-6,7-dihydro-4H- thieno[3,2-c]pyran-2-sulfonimidamide CHIRAL- PAK IG, 2*25 cm, 5 um 50% EtOH in Hex (0.1% FA) 418 790

(S) or (R)-N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-6,7-dihydro-4H- thieno[3,2-c]pyran-2-sulfonimidamide CHIRAL- PAK IG, 2*25 cm, 5 um 50% EtOH in Hex (0.1% FA) 418 791

(R) or (S)-3-(N′-((1,2,3,5,6,7-hexahydro-5- indacen-4-yl)carbamoyl)sulfamidimidoyl)- N-methylbenzenesulfonamide CHIRAL- PAK IE, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 449 792

(S) or (R)-3-(N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)sulfamidimidoyl)- N-methylbenzenesulfonamide CHIRAL- PAK IE, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 449 793

(S) or (R)-N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-2-((R)-2-hydroxy- 1-(2-methoxyethoxy)propan-2-yl)thiazole- 5-sulfonimidamide CHIRAL- PAK IA, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 495 794

(R) or (S)-N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-2-((R)-2-hydroxy- 1-(2-methoxyethoxy)propan-2-yl)thiazole- 5-sulfonimidamide CHIRAL- PAK IA, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 495 795

(R) or (S)-5-((cyclobutylamino)methyl)-3- fluoro-N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)thiophene-2- sulfonimidamide Chiralpak ID, 2*25 cm, 5 um 50% EtOH in Hex (0.1% FA) 463 796

(S) or (R)-5-((cyclobutylamino)methyl)-3- fluoro-N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)thiophene-2- sulfonimidamide Chiralpak ID, 2*25 cm, 5 um 50% EtOH in Hex (0.1% FA) 463 797

(R) or (S)-4- ((cyclobutyl(methyl)amino)methyl)-2- fluoro-N′-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3- yl)carbamoyl)benzenesulfonimidamide CHIRAL- PAK IG, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 457 798

(S) or (R)-4- ((cyclobutyl(methyl)amino)methyl)-2- fluoro-N′-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3- yl)carbamoyl)benzenesulfonimidamide CHIRAL- PAK IG, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 457 799

(R) or (S)-N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-5- phenylthiophene-2-sulfonimidamide CHIRAL- PAK ID, 4.6*50 mm, 5 um 30% EtOH in Hex (0.1% FA) 438 800

(S) or (R)-N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-5- phenylthiophene-2-sulfonimidamide CHIRAL- PAK ID, 4.6*50 mm, 5 um 30% EtOH in Hex (0.1% FA) 438 801

(S) or (R)-N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-5-(2- hydroxypropan-2-yl)-4-phenylthiophene-2- sulfonimidamide CHIRAL- PAK IA, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 496 802

(R) or (S)-N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-5-(2- hydroxypropan-2-yl)-4-phenylthiophene-2- sulfonimidamide CHIRAL- PAK IA, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 496 803

(R) or (S)-5-((dimethylamino)methyl)-N′- ((1,2,3,5,6,7-hexahydro-5-indacen-4- yl)carbamoyl)thiophene-2-sulfonimidamide CHIRAL- PAK IE, 2*25 cm, 5 um 50% EtOH in Hex (0.1% FA) 419 804

(S) or (R)-5-((dimethvlamino)methyl)-N′- ((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)thiophene-2-sulfonimidamide CHIRAL- PAK IE, 2*25 cm, 5 um 50% EtOH in Hex (0.1% FA) 419 805

(R) or (S)-5-(2-hydroxypropan-2-yl)-1- isopropyl-N′-((3-oxo-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide CHIRAL- PAK IG, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 460 806

(S) or (R)-5-(2-hydroxypropan-2-yl)-1- isopropyl-N′-((3-oxo-1,2,3,5,6,7- hexahydro-5-indacen-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide CHIRAL- PAK IG, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 460 807

(S) or (R)-4-(hydroxymethyl)-2-(2- hydroxypropan-2-yl)-N′-((3-oxo- 1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)thiazole-5-sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 465 808

(R) or (S)-4-(hydroxymethyl)-2-(2- hydroxypropan-2-yl)-N′-((3-oxo- 1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)thiazole-5-sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 465 809

(R) or (S)-4-(1-(dimethylamino)-2- methylpropan-2-yl)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)benzenesulfonimidamide CHIRAL- PAK IG, 3*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 455 810

(S) or (R)-4-(1-(dimethylamino)-2- methylpropan-2-yl)-N′-((1,2,3,5,6,7- hcxahydro-s-indaccn-4- yl)carbamoyl)benzenesulfonimidamide CHIRAL- PAK IG, 3*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 455 811

(R) or (S)-3-fluoro-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-5- isopropylpyridine-2-sulfonimidamide CHIRAL- PAK ID, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 417 812

(S) or (R)-3-fluoro-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-5- isopropylpyridine-2-sulfonimidamide CHIRAL- PAK ID, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 417 813

(R) or (S)-1-ethyl-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide CHIRAL- PAK IG, 2*25 cm, 5 um 40% MeOH (8 mM NH₃•MeOH) in CO₂ 374 814

(S) or (R)-1-ethyl-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide CHIRAL- PAK IG, 2*25 cm, 5 um 40% MeOH (8 mM NH₃•MeOH) in CO₂ 374 815

(R) or (S)-2-((S)-1,2-dihydroxypropan-2- yl)-N′-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3-yl)carbamoyl)thiazole- 5-sulfonimidamide CHIRAL- PAK IF, 4.6*50 mm, 3 um 20% EtOH in Hex (0.1% FA) 423 816

(S) or (R)-2-((S)-1,2-dihydroxypropan-2- yl)-N′-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3-yl)carbamoyl)thiazole- 5-sulfonimidamide CHIRAL- PAK IF, 4.6*50 mm, 3 um 20% EtOH in Hex (0.1% FA) 423 817

(R) or (S)-2-((R)-1,2-dihydroxypropan-2- yl)-N′-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3-yl)carbamoyl)thiazole- 5-sulfonimidamide CHIRAL- PAK IF, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 423 818

(S) or (R)-2-((R)-1,2-dihydroxypropan-2- yl)-N′-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3-yl)carbamoyl)thiazole- 5-sulfonimidamide CHIRAL- PAK IF, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 423 819

(R) or (S) -2-((R)-1,2-dihydroxypropan-2- yl)-N′-((3-oxo-1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)thiazole-5- sulfonimidamide (from Example 743) CHIRAL- PAK ID, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 451 820

(S) or (R)-2-((R)-1,2-dihydroxypropan-2- yl)-N′-((3-oxo-1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)thiazole-5- sulfonimidamide (from Example 743) CHIRAL- PAK ID, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 451 821

(R) or (S) -N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-5-((S)-pyrrolidin- 2-yl)thiophene-2-sulfonimidamide (separated from chiral Ex.730) CHIRAL- PAK IG, 2*25 cm, 5 um 40% EtOH in Hex (8 mM NH₃•MeOH) 431 822

(S) or (R) -N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-5-((S)-pyrrolidin- 2-yl)thiophene-2-sulfonimidamide (separated from chiral Ex.730) CHIRAL- PAK IG, 2*25 cm, 5 um 40% EtOH in Hex (8 mM NH₃•MeOH) 431 823

(R) or (S) -N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-5-((R)-pyriolidin- 2-yl)thiophene-2-sulfonimidamide (separated from chiml Ex.731) CHIRAL- PAK IG, 2*25 cm, 5 um 10% EtOH in Hex:DCM = 3:1 (10 mM NH₃—MeOH) 431 824

(S) or (R) -N′-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-5-((R)-pyrrolidin- 2-yl)thiophene-2-sulfommidamide (separated from chiral Ex.731) CHIRAL- PAK IG, 2*25 cm, 5 um 10% EtOH in Hex:DCM = 3:1 (10 mM NH₃— MeOH) 431 825

(R) or(S) -1-ethyl-N′-((2,4,5,6-tetrahydro- 1H-cyclobuta[f]inden-3-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide CHIRAL- PAK IE, 3*25 cm, 5 um 50% EtOH in Hex:DCM = 3:1 (10 mM NH₃—MeOH) 360 826

(S) or (R) -1-ethyl-N′-((2,4,5,6-tetrahydro- 1H-cyclobuta[f]inden-3-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide CHIRAL- PAK IE, 3*25 cm, 5 um 50% EtOH in Hex:DCM = 3:1 (10 mM NH₃— MeOH) 360 827

(R) or (S)-N′-((8-cyano-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)pyridine-2- sulfonimidamide CHIRAL- PAK IF, 2*25 cm, 5 um 45% EtOH (2 mM NH₃— MeOH) in CO₂ 440 828

(S) or (R)-N′-((8-cyano-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)pyridine-2- sulfonimidamide CHIRAL- PAK IF, 2*25 cm, 5 um 45% EtOH (2 mM NH₃— MeOH) in CO₂ 440 829

(S) or (R)-N′-((8-cyano-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-2-(1- hydroxy-2-methylpropan-2-yl)thiazole-5- sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 460 830

(R) or (S)-N′-((8-cyano-1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-2-(1- hydroxy-2-methylpropan-2-yl)thiazole-5- sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 460 831

(S) or (R)-6-(2-hydroxypropan-2-yl)-N′- ((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)pyridine-3-sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 429 832

(R) or (S)-6-(2-hydroxypropan-2-yl)-N′- ((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)pyridine-3-sulfonimidamide CHIRAL ART Cellulose- SB, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 833

(R) or (S)-3-fluoro-N′-((2,4,5,6-tetrahydro- 1H-cyclobuta[f]inden-3-yl)carbamoyl)- 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- sulfonimidamide CHIRAL- PAK IC, 2*25 cm, 5 um 15% MeOH in Hex:DCM = 3:1 (10 mM NH₃— MeOH) 421 834

(S) or (R)-3-fluoro-N′-((2,4,5,6-tetrahydro- 1H-cyclobuta[f]inden-3-yl)carbamoyl)- 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- sulfonimidamide CHIRAL- PAK IC, 2*25 cm, 5 um 15% MeOH in Hex:DCM = 3:1 (10 mM NH₃— MeOH) 421 835

(R) or (S)-3-fluoro-5-methyl-N′-((2,4,5,6- tetrahydro-1H-cyclobuta[f]inden-3- yl)carbamoyl)-4,5,6,7-tetrahydrothieno[3,2- c]pyridine-2-sulfonimidamide CHIRAL- PAK IE, 2*25 cm, 5 um 50% EtOH in Hex (0.1% FA) 435 836

(S) or (R)-3-fluoro-5-methyl-N′-((2,4,5,6- tetrahydro-1H-cyclobuta[f]inden-3- yl)carbamoyl)-4,5,6,7-tetrahydrothieno[3,2- c]pyridine-2-sulfonimidamide CHIRAL- PAK IE, 2*25 cm, 5 um 50% EtOH in Hex (0.1% FA) 435 837

(R) or (S)-4-((methylamino)methyl)-N′- ((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden- 3-yl)carbamoyl)thiophene-2- sulfonimidamide CHIRAL- PAK IG, 2*25 cm, 5 um 50% EtOH (8 mM NH₃•MeOH) in CO₂ 391 838

(S) or (R)-4-((methylamino)methyl)-N′- ((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden- 3-yl)carbamoyl)thiophene-2- sulfonimidamide CHIRAL- PAK IG, 2*25 cm, 5 um 50% EtOH (8 mM NH₃•MeOH) in CO₂ 391 839

(R) or (S)-1-(difluoromethyl)-4-fluoro-N′- ((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden- 3-yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide Chiralpak ID, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 400 840

(S) or (R)-1-(difluoromethyl)-4-fluoro-N′- ((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden- 3-yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide Chiralpak ID, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 400 841

(R) or (S)-3-fluoro-N′-((2,4,5,6-tetrahydro- 1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,7- dihydro-4H-thieno[3,2-c]pyran-2- sulfonimidamide CHIRAL- PAK IE, 2*25 cm, 5 um 50% EtOH in Hex (0.1% FA) 422 842

(S) or (R)-3-fluoro-N′-((2,4,5,6-tetrahydro- 1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,7- dihydro-4H-thieno[3,2-c]pyran-2- sulfonimidamide CHIRAL- PAK IE, 2*25 cm, 5 um 50% EtOH in Hex (0.1% FA) 422 843

(R) or (S)-5-(azetidin-1-ylmethyl)-3-fluoro- N′-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3- yl)carbamoyl)thiophene-2-sulfonimidamide CHIRAL- PAK IC, 2*25 cm, 5 um 50% EtOH in Hex (0.1% IPA) 435 844

(S) or (R)-5-(azetidin-1-ylmethyl)-3-fluoro- N′-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3- yl)carbamoyl)thiophene-2-sulfonimidamide CHIRAL- PAK IC, 2*25 cm, 5 um 50% EtOH in Hex (0.1% IPA) 435 845

(R/S, R)-4-(1-(cyclobutylamino)ethyl)-2- fluoro-N′-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3- yl)carbamoyl)benzenesulfonimidamide 1^(st) and 2^(nd) peak CHIRAL- PAK IG, 2*25 cm, 5 um 50% EtOH in Hex (8 mM NH₃•MeOH) 457 846

(R/S, S)-4-(1-(cyclobutylamino)ethyl)-2- fIuoro-N′-((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3- yl)carbamoyl)benzenesulfonimidamide 3^(rd) and 4^(th) peak CHIRAL- PAK IG, 2*25 cm, 5 um 50% EtOH in Hex (8 mM NH₃•MeOH) 457 847

(R, R) or (S, R) -4-(1- (cyclobutylamino)ethyl)-2-fluoro-N′- ((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden- 3-yl)carbamoyl)benzenesulfonimidamide (Separated from Ex. 832) Chiralpak AD, 2*25 cm, 5 um 20% EtOH in Hex (8 mM NH₃•MeOH) 457 848

(S, R) or (R, R) -4-(1- (cyclobutylamino)ethyl)-2-fluoro-N′- ((2,4,5,6-tetrahydro-1H-cyclobula[f]inden- 3-yl)carbamoyl)benzenesulfonimidamide (Separated from Ex. 832) Chiralpak AD, 2*25 cm, 5 um 20% EtOH in Hex (8 mM NH₃•MeOH) 457 849

(S, S) or (R, S) -4-(1- (cyclobutylamino)ethyl)-2-fluoro-N′- ((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden- 3-yl)carbamoyl)benzenesulfonimidamide (Separated from Ex. 833) Chiralpak AD, 2*25 cm, 5 um 30% EtOH in Hex (8 mM NH₃•MeOH) 457 850

(R, S) or (S, S) -4-(1- (cyclobutylamino)ethyl)-2-fluoro-N′- ((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden- 3-yl)carbamoyl)benzenesulfonimidamide (Separated from Ex. 833) Chiralpak AD, 2*25 cm, 5 um 30% EtOH in Hex (8 mM NH₃•MeOH) 457 851

(R, R) or (S, R)-N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-5-methoxy- 4,5,6,7-tetrahydrobenzo[c]thiophene-1- sulfonimidamide Column 2: CHIRALPAK IF, 2*25 cm, 5 um, 20% EtOH (10 mM NH₃MeOH) in (Hex:DCM = 3:1) to separate two fasting-co- eluting isomers from Column 1: CHIRALPAK ID 2*25 cm, 5 um, 50% EtOH (0.1% DEA) in (Hex/DCM 1/1) 446 852

(S, R) or (R, R)-N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-5-methoxy- 4,5,6,7-tetrahydrobenzo[c]thiophene-1- sulfonimidamide 446 853

(R, S) or (S, S)-N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-5-methoxy- 4,5,6,7-tetrahydrobenzo[c]thiophene-1- sulfonimidamide Column 2: CHIRALPAK ID, 2*25 cm, 5 um, 50% EtOH (10 mM NH₃—MeOH) in (Hex:DCM = 1:1) to separate two slow-co- eluting isomers from Column 1: CHIRALPAK ID 2*25 cm, 5 um, 50% EtOH (0.1% DEA) in (Hex/DCM 1/1) 446 854

(S, S) or (R, S)-N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-5-methoxy- 4,5,6,7-tetrahydrobenzo[c]thiophene-1- sulfonimidamide 446 855

(R, S) or (S, S)-N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-6-methoxy- 4,5,6,7-tetrahydrobenzo[c]thiophene-1- sulfonimidamide Column 2: CHIRALPAK IG, 2*25 cm, 5 um, 20% EtOH (10 mM NH₃—MeOH) in (Hex:DCM = 1:1) to separate two fasting-co- eluting isomers from Column 1: CHIRALPAK ID 2*25 cm, 5 um, MTBE (0.1% DEA): EtOH = 80:20 446 856

(S, S) or (R, S)-N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-6-methoxy- 4,5,6,7-tetrahydrobenzo[c]thiophene-1- sulfonimidamide 446 857

(R, R) or (S, R)-N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-6-methoxy- 4,5,6,7-tetrahydrobenzo[c]thiophene-1- sulfonimidamide Column 2: CHIRALPAK ID, 2*25 cm, 5 um, 20% EtOH in MTBE (10 mM NH₃—MeOH) to separate two slow-co- eluting isomers from Column 1: CHIRALPAK ID 2*25 cm, 5 um, MTBE (0.1% DEA): EtOH = 80:20 446 858

(S, R) or (R, R)-N′-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)-6-methoxy- 4,5,6,7-tetrahydrobenzo[c]thiophene-1- sulfonimidamide 446 859

(S, R) or (R, R)-2-fluoro-4-(1- methylpiperidin-3-yl)-N′-((2,4,5,6- tetrahydro-1H-cyclobuta[f]inden-3- yl)carbamoyl)benzenesulfonimidamide 1^(st) peak from CHIRALPAK IG, 2*25 cm, 5 um, 40% EtOH in Hex (8 mM NH₃•MeOH) 457 860

(R, S) or (S, S)-2-fluoro-4-(1- methylpiperidin-3-yl)-N′-((2,4,5,6- tetrahydro-1H-cyclobuta[f]inden-3- yl)carbamoyl)benzenesulfonimidamide Column 2: Reg-AD, 30*250 mm, 5 um, 15% IPA in Hex (8 mM NH₃•MeOH) to separate 2^(nd) and 3^(rd) peak from Column 1: CHIRALPAK IG, 2*25 cm, 5 um, EtOH in Hex (8 mM NH₃•MeOH) 457 861

(S, S) or (R, S)-2-fluoro-4-(1- methylpiperidin-3-yl)-N′-((2,4,5,6- tetrahydro-1H-cyclobuta[f]inden-3- yl)carbamoyl)benzenesulfonimidamide 457 862

(R, R) or (S, R)-2-fluoro-4-(1- methylpiperidin-3-yl)-N′-((2,4,5,6- tetrahydro-1H-cyclobuta[f]inden-3- yl)carbamoyl)benzenesulfonimidamide 4^(th) peak from CHIRALPAK IG, 2*25 cm, 5 um, EtOH in Hex (8 mM NH₃•MeOH) 457 863

(S/R, R)-4-(azetidin-2-yl)-N′-((1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl)benzenesulfonimidamide 1^(st) and 2^(nd) peak CHIRAL- PAK ID, 2*25 cm, 5 um 40% IPA in Hex:DCM = 3:1 (10 mM NH₃— MeOH) 411 864

(R, S) or (S, S)-4-(azetidin-2-yl)-N′- ((1,2,3,5,6,7-hexahydro-5-indacen-4- yl)carbamoyl)benzenesulfonimidamide 3^(rd) peak CHIRAL- PAK ID, 2*25 cm, 5 um 40% IPA in Hex:DCM = 3:1 (10 mM NH₃—MeOH) 411 865

(S, S) or (R, S)-4-(azetidin-2-yl)-N′- ((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)benzenesulfonimidamide 4^(th) peak CHIRAL- PAK ID, 2*25 cm, 5 um 40% IPA in Hex:DCM = 3:1 (10 mM NH₃— MeOH) 411 866

(S, R) or (R, R)-5- (cyclopropyl(methylamino)methyl)-N′- ((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden- 3-yl)carbamoyl)thiophene-2- sulfonimidamide (Separated from Ex. 720) CHIRAL- PAK IG, 2*25 cm, 5 um 40% EtOH in Hex (8 mM NH₃•MeOH) 416 867

(S, S) or (R, S)-5- (cyclopropyl(methylamino)methyl)-N′- ((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden- 3-yl)carbamoyl)thiophene-2- sulfonimidamide (Separated from Ex. 720) CHIRAL- PAK IG, 2*25 cm, 5 um 40% EtOH in Hex (8 mM NH₃•MeOH) 416 868

(R, R) or (S, R)-5- (cyclopropyl(methylamino)methyl)-N′- ((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden- 3-yl)carbamoyl)thiophene-2- sulfonimidamide (Separated from Ex. 721) CHIRAL- PAK IG, 2*25 cm, 5 um 40% EtOH in Hex (8 mM NH₃•MeOH) 416 869

(R, S) or (S, S)-5- (cyclopropyl(methylamino)methyl)-N′- ((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden- 3-yl)carbamoyl)thiophene-2- sulfonimidamide (Separated from Ex. 721) CHIRAL- PAK IG, 2*25 cm, 5 um 40% EtOH in Hex (8 mM NH₃•MeOH) 416 870

(R) or (S) -3-fluoro-4- ((methylamino)methyl)-N′-((2,4,5,6- tetrahydro-1H-cyclobuta[f]inden-3- yl)carbamoyl)thiophene-2-sulfonimidamide CHIRAL- PAK IC, 3*25 cm, 5 um 30% IPA in Hex:DCM = 3:1 (10 mM NH₃— MeOH) 409 871

(S) or (R) -3-fluoro-4- ((methylamino)methyl)-N′-((2,4,5,6- tetrahydro-1H-cyclobuta[f]inden-3- yl)carbamoyl)thiophene-2-sulfonimidamide CHIRAL- PAK IC, 3*25 cm, 5 um 30% IPA in Hex:DCM = 3:1 (10 mM NH₃— MeOH) 409 872

(R) or (S) -5-(2,2-difluoroethyl)-N′- ((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden- 3-yl)carbamoyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2- sulfonimidamide CHIRAL- PAK ID, 2*25 cm, 5 um 10% IPA in Hex:DCM = 3:1 (10 mM NH₃—MeOH) 467 873

(S) or (R) -5-(2,2-difluoroethyl)-N′- ((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden- 3-yl)carbamoyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2- sulfonimidamide CHIRAL- PAK ID, 2*25 cm, 5 um 10% IPA in Hex:DCM = 3:1 (10 mM NH₃— MeOH) 467 874

(R or S,4S)-4-(difluoromethyl)-N′- ((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden- 3-yl)carbamoyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2- sulfonimidamide Resolved from Example 782 CHIRAL- PAK IC, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 453 875

(S or R,4S)-4-(difluoromethyl)-N′- ((2,4,5,6-tetrahydro-1H-cyclobula[f]inden- 3-yl)carbamoyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2- sulfonimidamide Resolved from Example 782 CHIRAL- PAK IC, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 453 876

(R or S,4R)-4-(difluoromethyl)-N′- ((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden- 3-yl)carbamoyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2- sulfonimidamide Resolved from Example 783 CHIRAL- PAK IE, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 453 877

(S or R,4R)-4-(difluoromethyl)-N′- ((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden- 3-yl)carbamoyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2- sulfonimidamide Resolved from Example 783 CHIRAL- PAK IE, 2*25 cm, 5 um 30% EtOH in Hex (0.1% FA) 453 As a convention, the faster-eluting enantiomer is always listed first in the table followed by the slower-eluting enantiomer of the pair. The symbol * at a chiral center denotes that this chiral center has been resolved and the absolute stereochemistry at that center has not been determined. Assigned stereochemistry in compound names are tentative. Some carbon stereocenters were assigned arbitrarily for registration purpose, such as the carbon centers for Examples 874-877.

TABLE 76 Examples in the following table were prepared using similar conditions as described in Example 735 and Scheme XX from appropriate starting materials. Ex. Exact Mass # Compound # Structure IUPAC Name [M + H]⁺ 878 1100

3-Fluoro-N′- ((1,2,3,5,6,7-hexahydro- s-indacen-4- yl)carbamoyl)-4-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide 438 879 1101

3-Fluoro-4-(2- hydroxypropan-2-yl)-N′- ((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3- yl)carbamoyl)thiophene- 2-sulfonimidamide 424

TABLE 77 Examples in the following table were obtained from chiral HPLC resolutions of racemic examples described above. TheF chiral column and eluents are listed in the table. LC-MS Ex. # Compound # Structure IUPAC Name Column Eluents [M + H]⁺ 880 1102

(R) or (S)-3-fluoro-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide Chiralpak ID, 2*25 cm, 5 um 50% IPA in Hex (0.1% FA) 438 881 1103

(S) or (R)- 3-fluoro-N′- ((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide Chiralpak ID, 2*25 cm, 5 um 50% IPA in Hex (0.1% FA) 438 882 1104

(R) or (S)- 3-fluoro-4-(2- hydroxypropan-2-yl)-N′- ((2,4,5,6-tetrahydro-1H- cyclobuta[f]inden-3- yl)carbamoyl)thiophene-2- sulfonimidamide CHIRALPAK IF, 2*25 cm, 5 um 20% EtOH in Hex (0.1% FA) 424 883 1105

(S) or (R)- 3-fluoro-4-(2- hydroxypropan-2-yl)-N′- ((2,4,5,6-tetrahvdro-1H- cyclobuta[f]inden-3- yl)carbamoyl)thiophene-2- sulfonimidamide CHIRALPAK IF, 2*25 cm, 5 um 20% EtOH in Hex (0.1% FA) 424 As a convention, the faster-eluting enantiomer is always listed first in the table followed by the slower-eluting enantiomer of the pair. The symbol * at a chiral center denotes that this chiral center has been resolved and the absolute stereochemistry at that center has not been determined. Assigned stereochemistry in compound names are tentative.

The following protocol is suitable for testing the activity of the compounds disclosed herein.

Procedure 1: IL-1β Production in PMA-Differentiated THP-1 Cells Stimulated with Gramicidin.

THP-1 cells were purchased from the American Type Culture Collection and sub-cultured according to instructions from the supplier. Cells were cultured in complete RPMI 1640 (containing 10% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 μg/ml)), and maintained in log phase prior to experimental setup. Prior to the experiment, compounds were dissolved in dimethyl sulfoxide (DMSO) to generate a 30 mM stock. The compound stock was first pre-diluted in DMSO to 3, 0.34, 0.042 and 0.0083 mM intermediate concentrations and subsequently spotted using Echo550 liquid handler into an empty 384-well assay plate to achieve desired final concentration (e.g. 100, 33, 11, 3.7, 1.2, 0.41, 0.14, 0.046, 0.015, 0.0051, 0.0017 μM). DMSO was backfilled in the plate to achieve a final DMSO assay concentration of 0.37%. The plate was then sealed and stored at room temperature until required.

THP-1 cells were treated with PMA (Phorbol 12-myristate 13-acetate) (20 ng/ml) for 16-18 hours. On the day of the experiment the media was removed and adherent cells were detached with trypsin for 5 minutes. Cells were then harvested, washed with complete RPMI 1640, spun down, and resuspended in RPMI 1640 (containing 2% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 μg/ml). The cells were plated in the 384-well assay plate containing the spotted compounds at a density of 50,000 cells/well (final assay volume 50 μl). Cells were incubated with compounds for 1 hour and then stimulated with gramicidin (5 μM) (Enzo) for 2 hours. Plates were then centrifuged at 340 g for 5 min. Cell free supernatant (40 μL) was collected using a 96-channel PlateMaster (Gilson) and the production of IL-1β was evaluated by HTRF (cisbio). The plates were incubated for 18 h at 4° C. and read using the preset HTRF program (donor emission at 620 nm, acceptor emission at 668 nm) of the SpectraMax i3x spectrophotometer (Molecular Devices, software SoftMax 6). A vehicle only control and a dose titration of CRID3 (100-0.0017 μM) were run concurrently with each experiment. Data was normalized to vehicle-treated samples (equivalent to 0% inhibition) and CRID3 at 100 μM (equivalent to 100% inhibition). Compounds exhibited a concentration-dependent inhibition of IL-1β production in PMA-differentiated THP-1 cells.

Procedure 2: IL-1β Production in PMA-Differentiated THP-1 Cells Stimulated with Gramicidin.

THP-1 cells were purchased from the American Type Culture Collection and sub-cultured according to instructions from the supplier. Prior to experiments, cells were cultured in complete RPMI 1640 (containing 10% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 μg/ml)), and maintained in log phase prior to experimental setup. Prior to the experiment THP-1 were treated with PMA (Phorbol 12-myristate 13-acetate) (20 ng/ml) for 16-18 hours. Compounds were dissolved in dimethyl sulfoxide (DMSO) to generate a 30 mM stock. On the day of the experiment the media was removed and adherent cells were detached with trypsin for 5 minutes. Cells were then harvested, washed with complete RPMI 1640, spun down, resuspended in RPMI 1640 (containing 2% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 μg/ml) . The cells were plated in a 384-well plate at a density of 50,000 cells/well (final assay volume 50 μl). Compounds were first dissolved in assay medium to obtain a 5× top concentration of 500 μM. 10 step dilutions (1:3) were then undertaken in assay medium containing 1.67% DMSO. 5× compound solutions were added to the culture medium to achieve desired final concentration (e.g. 100, 33, 11, 3.7, 1.2, 0.41, 0.14, 0.046, 0.015, 0.0051, 0.0017 μM). Final DMSO concentration was at 0.37%. Cells were incubated with compounds for 1 hour and then stimulated with gramicidin (5 μM) (Enzo) for 2 hours. Plates were then centrifuged at 340 g for 5 min. Cell free supernatant (40 μL) was collected using a 96-channel PlateMaster (Gilson) and the production of IL-1β was evaluated by HTRF (cisbio). A vehicle only control and a dose titration of CRID3 (100-0.0017 μM) were run concurrently with each experiment. Data was normalized to vehicle-treated samples (equivalent to 0% inhibition) and CRID3 at 100 μM (equivalent to 100% inhibition). Compounds exhibited a concentration-dependent inhibition of IL-1β production in PMA-differentiated THP-1 cells.

Procedure 3

-   1. Experimental Procedure

1.1 Cell Culture

-   -   1) Culture THP-1 cells in the complete RPMI-1640 medium with 10%         FBS at 37° C., 5% CO₂.     -   2) Passage the cells every 3 days by inoculating 3×10⁵ cells per         ml.

1.2 Compound Preparation

-   -   Prepare the 3-fold serial dilution of the compounds with DMSO in         a 384-well LDV Microplate using TECAN EVO system to generate the         compound source plate with 10 concentrations. Top concentration         is 30 mM. FIG. 3 depicts the layout of the microplate.

1.3 Cell Preparation

-   -   1) Centrifuge THP-1 cells at 350 g for 5 min.     -   2) Re-suspend cells with complete RMPI-1640 medium, and count         cells.     -   3) Seed cells in T225 flask, about 2.5×10⁷ per flask, treat         cells with 20 ng/ml PMA (final DMSO concentration<1%).     -   4) Incubate overnight.

1.4 THP-1 Stimulation

-   -   1) Wash adherent THP-1 cells with PBS, and detach cells with 4         ml trypsin for T225 flask.     -   2) Centrifuge cells at 350 g for 5 min, re-suspend cells with         RPMI-1640 containing 2% FBS and count cells with trypan blue.     -   3) Transfer 50 nl/well the serial dilution of test compound to         384-well plate by Echo; For the high control and first point of         CRID3 (MCC950), transfer 165 nl, then backfill to make the DMSO         concentration is consistent in all wells, the plate layout is as         below.     -   4) Seed 50 k cells in 40 ul RPMI-1640 with 2% FBS per well in         384-well plate.     -   5) Incubate for 1 h at 37° C., 5% CO₂.     -   6) Prepare 5× gramicidin, add 10 μl per well, the final         concentration is 5 μM, incubate for 2 hrs at 37° C., 5% CO₂.     -   7) Centrifuge at 350 g for 1 min.     -   8) Pipet 16 μl supernatant by apricot, and transfer into white         384 proxiplate. FIG. 3 depicts the layout of the plates: HC: 100         μM CRID3 (MCC950)+5 μM gramicidin LC: 5 μM Gramicidin.

1.5 IL-1β Detection

-   -   1) Homogenize the 5× diluent #5 with a vortex and add 1 volume         of stock solution in 4 volumes of distilled water.     -   2) Thaw 20× stock solution of anti-IL1β-Cryptate-antibody and         anti-IL1β XL-antibody. Dilute these two antibodies to 1× with         detection buffer #3.     -   3) Pre-mix the two ready-to-use antibody solutions just prior to         use.     -   4) Dispense 4 ul of pre-mixed Anti-IL1β antibodies working         solution into all wells.     -   5) Seal the plate and incubate overnight at 4° C.     -   6) Read the cell plate using EnVison and plot Readout vs. the         test compound concentration to calculate the IC₅₀.

-   2. Data Analysis:

-   1. IC₅₀ of compounds can be calculated using the following formulas

Formula for IC₅₀

inhibition=100-100×[HC_(ave)−Readout/(HC_(ave)−LC_(ave))]

-   2. Fit the normalized data in a dose-response manner using XLfit,     and calculate the compound concentration.     Tables B1, B2, and B3 show the biological activity of compounds in     hTHP-1 assay containing 2% fetal bovine serum. Table B4 shows the     biological activity of compounds in hTHP-1 assay containing 10%     fetal bovine serum. Key: <0.008 μM=“++++++”; ≥0.008 and <0.04     μM=“+++++”; ≥0.04 and <0.2 μM=“++++”; ≥0.2 and <1 μM=“+++”; ≥1 and     <5 μM=“++”; ≥5 and <30 μM=“+”.

TABLE B1 Average IC₅₀ of compounds in hTHP-1 assay Example # Compd # hTHP-1 IC₅₀ (μm) 1 181 +++++ 2  181a +++++ 3  181b +++ 4  101′ ++++ 5 101 or 102 +++ 6 102 or 101 +++++ 7 194 +++ 8 270 + 9 204 >30 10 180 ++++ 11 190 + 12 182 ++++ 13 191 ++++ 14 177 +++++ 15 185 ++++ 16 186 ++++ 17 187 +++++ 18 188 +++ 19 192 ++ 20 189 ++++ 21 178 ++++ 22 193 ++ 23 170 ++++ 24 168 ++ 25 171 ++++ 26 122 ++++ 27 120 +++ 28 125 ++++ 29 129 + 30 213 +++++ 31 207 ++++ 32 195 +++++ 33 179 ++++ 34 105 ++ 35 121 +++ 36 145 ++ 37 131 ++ 38 132 ++++ 39 144 +++ 40 149 ++++ 41 152 ++++ 42 150 + 43 167 ++++ 44 106 +++++ 45 107 ++++++ 46 110 ++ 47 151 +++ 48 154 ++++ 49 148 +++ 50 153 ++ 51 109 ++ 52 135 +++ 53 134 +++++ 54 130 ++ 55 212 +++ 56 205 +++ 57 143 +++ 58 206 ++ 59 108 +++++ 60 202 ++ 61 208 +++++ 62 197 ++++ 63 196 ++ 64 124 ++++ 65 173 ++++ 66 172 + 67 174 +++ 68 158 ++ 69 220 ++ 70 157 ++ 71 161 ++ 72 159 +++ 73 165 ++ 74 183 +++++ 75 176 +++++ 76 136 +++++ 77 209 ++++ 78 203 >30 79 180b or 180a +++++ 80 180a or 180b +++ 81  179b +++++ 82  179a +++ 83 190a or 190b ++ 84 190b or 190a >30 85 182a or 182b +++++ 86 182b or 182a +++ 87 191b or 191a ++++ 88 191a or 191b ++ 89 177b or 177a +++++ 90 177a or 177b +++ 91 185b or 185a ++++ 92 185a or 185b ++ 93 186a or 186b ++++ 94 186b or 186a ++ 95 187a or 187b ++++++ 96 187b or 187a +++ 97 188b or 188a ++++ 98 188a or 188b + 99 192b or 192a +++ 100 192a or 192b + 101 189b or 189a ++++ 102 189a or 189b ++ 103 178b or 178a ++++ 104 178a or 178b ++ 105 193b or 193a +++ 106 193a or 193b + 107 170b or 170a + 108 170a or 170b ++++ 109 168b or 168a +++ 110 168a or 168b >30 111 171b or 171a ++++ 112 171a or 171b + 113 122b or 122a +++++ 114 122a or 122b ++ 115 120b or 120a ++ 116 120a or 120b ++++ 117 125b or 125a ++++ 118 125a or 125b ++ 119 129b or 129a + 120 129a or 129b >30 121 112b or 112a +++++ 122 112a or 112b +++ 123  207c ++++ 124  207aa ++ 125  207b ++++ 126 195a or 195e ++ 127 195e or 195a ++++ 128 105b or 105a +++ 129 105a or 105b + 130 121b or 121a ++++ 131 121a or 121b ++ 132 145b or 145a ++ 133 145a or 145b >30 134 131b or 131a >30 135 131a or 131b ++ 136 225b or 225a ++ 137 225a or 225b ++++ 138 144b or 144a ++ 139 144a or 144b ++++ 140 149b or 149a +++++ 141 149a or 149b ++ 142 152b or 152a ++++ 143 152a or 152b + 144 151b′ or 151a′ >30 145 151a′ or 151b′ + 146 167b or 167a ++ 147 167a or 167b +++ 148 107b or 107a ++++++ 149 107a or 107b +++ 150 110b or 110a + 151 110a or 110b +++ 152 151b or 151a ++++ 153 151a or 151b ++ 154 154b or 154a ++++ 155 154a or 154b ++ 156 148b or 148a +++ 157 148a or 148b + 158 153b or 153a ++ 159 153a or 153b + 160 109b or 109a +++ 161 109a or 109b + 162 135b or 135a +++ 163 135a or 135b + 164 134b or 134a +++++ 165 134a or 134b ++ 166 130b or 130a +++ 167 130a or 130b    >11.2150 168 212b or 212a +++ 169 212a or 212b     >5.5915 170 205b or 205a ++ 171 205a or 205b +++ 172 143b or 143a +++ 173 143a or 143b ++ 174 206b or 206a +++ 175 206a or 206b ++ 176 108b or 108a +++++ 177 108a or 108b ++ 178 202b or 202a + 179 202a or 202b ++ 180 116b or 116a ++ 181 116a or 116b + 182 173a or 173b +++++ 183 173b or 173a +++ 184 174b or 174a +++ 185 174a or 174b + 186 223b or 223a ++++ 187 223a or 223b + 188 158b or 158a ++ 189 158a or 158b >30 190 220b or 220a +++ 191 220a or 220b + 192 157a or 157b +++ 193 157b or 157a >30 194 161b or 161a ++ 195 161a or 161b + 196 165b or 165a + 197 165a or 165b >30 198 172b or 172a + 199 172a or 172b >30 200 106a or 106b +++++ 201 106b or 106a +++ 202 136b or 136a ++ 203 136a or 136b ++++++ 204 183a or 183b +++ 205 183b or 183a +++++ 206 176b or 176a +++++ 207 176a or 176b +++ 208 221 + 209 219 >30 210 217 >30 211 216 + 212 215 >30 213 218 >30 214 214 >30 215 211 + 216 210 >30 217 201 + 218 200 ++ 219 199 >30 220 198 + 221 141 ++++ 222 140 +++ 223 321 +++++ 224 321b or 321a +++++ 225 321a or 321b ++ 226 329 +++++ 227 375 ++++ 228 376 ++++ 229 307 ++ 230 323 ++ 231 338 ++ 232 341 ++ 233 342 ++ 234 345 ++ 235 346 ++ 236 347 ++ 237 348 ++ 238 403 ++ 239 402 ++ 240 350 ++ 241 322 ++ 242 351 ++ 243 358 ++ 244 401 + 245 404 + 246 331 + 247 339 + 248 405 + 249 406 □□□□□□ 250 324 + 251 407 ++ 252 410 >30 253 408 254 308 ++ 255 311 + 256 312 >30 257 327 ++++ 258 326 ++++ 259 139 +++ 260 137 +++ 261 409 ++ 262 303 +++++ 263 325 +++++ 264 138 ++ 265 332 ++++ 266 334 ++++ 267 335 ++++ 268 337 ++ 269 113 +++++ 270 343 ++ 271 349 ++ 272 344 +++ 273 359 + 274 352 +++ 275 354 ++ 276 355 +++ 277 356 >30 278 357 +++ 279 340 +++++ 280 377 +++ 281 378 +++++ 282 379 +++ 283 380 +++ 284 353 + 285 333 ++++ 287 382 ++ 288 383 ++ 289 315 ++++ 290 316 ++ 291 317 ++++ 292 319 ++++ 293 320 +++ 294 336 ++++ 295 330 ++++ 296  364a ++++++ 297  364b +++ 298  365a ++++ 299  365b ++ 300  308a +++ 301  308b + 302 195ba or 195bb +++ 303 195bb or 195ba +++++ 304  207a or 207bb ++++ 305 207bb or 207a  +++++ 306  366a ++++++ 307  366b ++++ 308  139a ++ 309  139b ++++ 310  367a +++++ 311  367b +++ 312  409b ++ 313  409a ++ 314  369a +++ 315  369b + 316  159a +++ 317  159ab ++ 318  159ba +++ 319  137a ++ 320  137b ++++ 321  317ab ++ 322  317aa +++ 323  317bb ++++ 324  317ba +++++ 325  316a    >28.4352 326  316b + 327  373a >30 328  373b ++ 329  374a >30 330  374b >30 331  319ab + 332  319aa +++ 333  319bb ++ 334  319ba +++++ 335  320a ++ 336  320b +++ 337  323ab ++ 338  323bb ++ 339  323aa ++ 340  323ba ++ 341  303a ++++++ 342  303b +++ 343  315a ++++ 344  315b ++ 345  138a +++ 346  138b + 347  328a +++++ 348  328b ++ 349  326b ++ 350  326a ++++ 351  318a +++ 352  318b ++++ 353  325a ++ 354  325b +++++ 355  329a ++++++ 356  329b +++ 357  404b + 358  404a >30 359  332a +++++ 360  332b +++ 361  335a ++++ 362  335b ++ 363  336a ++ 364  336b ++++ 365  337a >30 366  337b ++ 367  371a >30 368  371b ++ 369  372a >30 370  372b +++ 371  334a + 372  334b ++++ 373  339a + 374  339b +++++ 375  334ab + 376  334aa + 377  334bb ++++ 378  334ba +++ 379  338a ++ 380  338b >30 381  340a +++++ 382  340b ++ 383  361b >30 384  361a >30 385  113a +++++ 386  113b +++ 387  330a ++ 388  330b ++++ 389  341a >30 390  341b ++ 391  360ba +++ 392  360bb +++ 393  363b +++++ 394  363a +++ 395  343a ++ 396  343b >30 397  359a ++ 398  359b >30 399  352a +++ 400  352b + 401  383a >30 402  383b ++ 403  382a +++ 404  382b + 405  379a 406  379b >30 407  380a + 408  380b ++ 409  380c +++ 410  380d ++++ 411  384a ++ 412  384b >30 413  357a +++ 414  357b + 415  354a >30 416  354b +++ 417  387a ++ 418  387b ++++ 419  333a ++++ 420  333b ++ 421  375a +++++ 422  375b 423  376a +++++ 424  376b 425 318 +++ 426 313 + 427 314 + 428 309 + 430 310 + 431 306 + 411 ++++  411a ++++ 412 ++++  412a ++++ 413 +++  413a ++++

TABLE B2 Example # Compound # IC₅₀ (uM) 432 378a +++++ 433 378b +++ 434 858  +++ 435 837  + 436 829  +++++ 437 842  ++ 438 859  +++ 439 873  ++ 440 834  +++ 441 869c +++ 442 817  +++ 443 411  ++++ 444 802  ++ 445 870a ++++ 446 846  +++ 447 847  ++ 448 814  ++ 449 845  ++ 450 857  ++++ 451 853  +++ 452 826  ++ 453 840  ND 454 805  +++ 455 851  ++ 456 818  +++ 457 816  +++ 458 828  ++ 459 843  ++ 460 801  ++++ 461 806  +++ 462 807  ++ 463 808  ++ 464 852  ++ 465 803  ++++ 466 811  +++ 467 835  ++++ 468 836  ++++ 469 804  ++ 470 822  +++ 471 871d ++++ 472 872a ++++ 473 815  ++++ 474 819  ++ 475 820  ++++ 476 501  +++ 477 821  +++ 478 833  +++ 479 413  +++ 480 831  ++ 481 412  ++++ 482 849  ++ 483 850  ++ 484 854  +++ 485 855  ++ 486 860  ++ 487 861  ++ 488 862  + 489 863  + 490 844  +++ 491 414  ++ 492 856  ++ 493 841  + 494 812  +++ 495 810  ++ 496 813  ++ 497 809  ++ 498 803b +++++ 499 909  ++++ 500 838  + 501 838e + 502 838b +++ 503 832  ++ 504 830  + 505 825  + 506 824  + 507 823  + 508 848  + 509 868f  >30 510 867f  +++ 511 867e >30 512 868e ++ 513 839  + 514 865a ++ 515 869a ++++ 516 869b ++ 517 809b + 518 809a ++ 519 813b ++ 520 813a + 521 803a ++ 522 806a +++ 523 806b + 524 808b +++ 525 808a + 526 812b +++ 527 812a ++ 528 810b +++ 529 810a + 530 811b ++++ 531 811a ++ 532 805a ++ 533 805b +++ 534 871b +++++ 535 871a ++ 536 814b + 537 814a ++ 538 815b + 539 815a ++++ 540 866a ++ 541 866b ++++ 542 820b ++ 543 820a +++++ 544 822b + 545 822a ++++ 546 501b +++ 547 501a ++ 548 817b ++++ 549 817a + 550 832b ++ 551 832a >30 552 821a ++++ 553 821b + 554 833b + 555 833a +++ 556 834b + 557 834a ++++ 558 413a ++++ 559 413b ++ 560 835b +++++ 561 835a +++ 562 836b ++ 563 836a ++++ 564 837b >30 565 837a + 566 828a ++ 567 828b + 568 873b + 569 873a ++++ 570 412a +++++ 571 412b +++ 572 840b +++ 573 840a + 574 844b + 575 844a +++ 576 841b + 577 841a >30 578 849b ++ 579 849a + 580 846b +++ 581 846a + 582 845a +++ 583 845b + 584 349b >30 585 349a ++ 586 850b >30 587 850a >30 588 851b >30 589 851a ++ 590 852b >30 591 852a ++ 592 853b + 593 853a +++ 594 855b >30 595 855a ++ 596 857b ++ 597 857a ++++ 598 858b +++ 599 858a + 600 859b +++ 601 859a + 602 860b +++ 603 860a + 604 377b >30 605 377a +++ 605 377a +++ 606 344a +++ 607 344b >30 608 861b >30 609 861a >30 610 322a ++ 611 322b >30 612 862b >30 613 862a >30 614 863b >30 615 863a + 616 355b + 617 355a +++ 618 356b >30 619 356a >30 620 346a ++ 621 346b >30 622 838f  >30 623 838d >30 624 838c +++ 625 838a +++ 626 829b +++++ 627 829c +++ 628 829a +++ 629 411a ++++ 630 411b +++++ 631 411e ++ 632 411d + 633 411c + 634 842a +++ 635 842b + 636 842d ++++ 637 842c +++ 638 826f  ++ 639 826d >30 640 826b ++ 641 826a ++ 642 826e + 643 826c >30 644 819d +++ 645 819c >30 646 819b >30 647 819a +++ 648 847b ++ 649 847a + 650 847b + 651 867d ++ 652 867c ++ 653 867b + 654 867a >30 655 868d >30 656 868c >30 657 868b ++ 658 868a + 659 854d + 660 854c +++ 661 854b +++ 662 854a +++ 663 864a >30 664 856e +++ 665 856d >30 666 856c >30 667 856b +++ 668 856a ++ 669 901  ++++ 670 901a ++++ 671 901b ++ 672 910  ++++ 673 922a ++++ 674 896  ++++ 675 894  ++++ 676 894a ++++ 677 918a ++++ 678 905  + 679 915  +++ 680 912  +++++ 681 906  +++ 682 897  +++ 683 923a +++ 684 924a ++++ 685 912b +++++ 686 912a ++ 687 906b ++++ 688 906a ++ 691 910b ++++ 692 910a ++ 693 897a +++ 694 897b + 695 872c ++++ 696 872b +++ 697 870c ++++ 698 870b ++ 699 885a ++ 700 884a ++ 701 883a ++ 702 882a ++ 703 880a ++ 704 879a ++ 705 878a ++ 706 877a ++ 707 876a ++ 708 881a ++ 709 827a +++ 710 875a ++++ 711 875b ++ 712 886a + 713 874b +++++ 714 874a +++++ 802a +++ 802b + 802c + 804b +++ 804a >30 818a ++ 818b +++ 875  887a + 887b >30 888a 889  ++ 889a + 889b +++ 890  + 891  ++ 892  +++ 893  ++++ 895  ++ 898  +++ 899  + 900  ++++ 902  ++ 902a >30 902b +++ 903  ++ 903a +++ 903b + 904  +++ 904a ++++ 904b ++ 907  ++ 908  +++ 908a >30 908b +++ 911  ++ 911a >30 911b ++ 911c >30 911d ++ 913  ++++ 913a ++ 913b ++++ 914  ++ 914a + 914b ++ 916  +++ 916a ++++ 916b ++ 917  + 919a +++ 919b +++++ 919c +++++ 919d +++ 919e +++++ 919f  +++++ 920a >30 920b +++ 920c ++++ 920d +++ 921a + 921b +++ 921c ++ 921d +++ 921e +++ 921f  +++

TABLE B3 Example # hTHP-1 IC₅₀ 715 ++++ 716 +++++ 717 +++ 718 +++ 719 +++++ 720 +++++ 721 +++++ 722 ++++ 723 ++++ 724 ++++ 725 +++ 726 +++ 727 ++ 728 +++ 729 ++ 730 +++ 731 +++ 732 +++++ 733 ++++ 734 ++++ 735 ++ 736 +++ 737 +++ 738 ++ 739 ++ 740 +++ 741 +++++ 742 +++++ 743 +++ 744 ++++ 745 ++ 746 +++ 747 +++ 748 ++++ 749 +++ 750 + 751 ++ 752 ++ 753 ++++ 754 ++++ 755 +++ 756 ++++ 757 ++++ 758 +++ 759 + 760 +++ 761 +++ 762 + 763 ++ 764 ++ 765 ++ 766 ++ 767 ++++ 768 +++ 769 ++++ 770 +++ 771 +++ 772 ++++ 773 ++ 774 ++ 775 ++ 776 + 777 ++++ 778 +++ 779 ++++ 780 ++ 781 ++++ 782 +++ 783 +++ 784 +++++ 787 ++++ 788 +++ 789 +++ 790 + 791 +++ 792 ++ 793 ++ 794 +++++ 795 +++ 796 + 797 +++ 798 >30 799 >30 800 >30 801 + 802 ++++ 803 +++ 804 + 805 +++ 806 >30 807 + 808 ++ 809 +++ 810 + 811 +++ 812 + 813 ++++ 814 ++ 815 +++++ 816 +++ 817 +++++ 818 +++ 819 +++ 820 + 821 +++ 822 ++ 823 +++ 824 + 825 ++++ 826 ++ 827 +++ 828 ++ 829 ++ 830 ++++ 831 >30 832 +++ 833 +++++ 834 +++ 835 ++++ 836 ++ 837 ++++ 838 +++ 839 ++++ 840 ++ 841 +++ 842 + 843 ++++ 844 ++ 845 +++ 846 ++ 847 +++ 848 +++ 849 + 850 + 851 +++ 852 ++ 853 >30 854 + 855 >30 856 >30 857 ++ 858 + 859 ++ 860 >30 861 >30 862 ++ 863 +++ 864 + 865 + 866 +++++ 867 ++ 868 +++++ 869 +++ 870 ++++ 871 ++ 872 ++ 873 >30 874 ++++ 875 ++ 876 ++++ 877 ++

TABLE B4 Example # hTHP-1 IC₅₀ in 10% FBS 878 ++++ 879 ++++ 880 ++++ 881 + 882 +++++ 883 ++

Study Example 1

The CARD8 gene is located within the inflammatory bowel disease (IBD) 6 linkage region on chromosome 19. CARD8 interacts with NLRP3, and Apoptosis-associated Speck-like protein to form a caspase-1 activating complex termed the NLRP3 inflammasome. The NLRP3 inflammasome mediates the production and secretion of interleukin-1β, by processing pro-IL-10 into mature secreted IL-1β. In addition to its role in the inflammasome, CARD8 is also a potent inhibitor of nuclear factor NF-κB. NF-κB activation is essential for the production of pro-IL-1β. Since over-production of IL-1β and dyregulation of NF-κB are hallmarks of Crohn's disease, CARD8 is herein considered to be a risk gene for inflammatory bowel disease. A significant association of CARD8 with Crohn's disease was detected in two British studies with a risk effect for the minor allele of the non-synonymous single-nucleotide polymorphism (SNP) of a C allele at rs2043211. This SNP introduces a premature stop codon, resulting in the expression of a severely truncated protein. This variant CARD8 protein is unable to suppress NF-κB activity, leading to constitutive production of pro-IL-10 , which is a substrate for the NLRP3 inflammasome. It is believed that a gain-of-function mutation in an NLRP3 gene (e.g., any of the gain-of-function mutations described herein, e.g., any of the gain-of-function mutations in an NLRP3 gene described herein) combined with a loss-of-function mutation in a CARD8 gene (e.g., a C allele at rs2043211) results in the development of diseases related to increased NLRP3 inflammasome expression and/or activity. Patients having, e.g., a gain-of-function mutation in an NLRP3 gene and/or a loss-of-function mutation in a CARD8 gene are predicted to show improved therapeutic response to treatment with an NLRP3 antagonist.

A study is designed to determine: whether NLRP3 antagonists inhibit inflammasome function and inflammatory activity in cells and biopsy specimens from patients with Crohn's disease or ulcerative colitis; and whether the specific genetic variants identify patients with Crohn's disease or ulcerative colitis who are most likely to respond to treatment with an NLRP3 antagonist.

The secondary objectives of this study are to: determine if an NLRP3 antagonist reduces inflammasome activity in Crohn's disease and ulcerative biopsy samples (comparing Crohn's disease and ulcerative colitis results with control patient results); determine if an NLRP3 antagonist reduced inflammatory cytokine RNA and protein expression in Crohn's disease and ulcerative colitis samples; determine if baseline (no ex vivo treatment) RNA levels of NLRP3, ASC, and IL-1β are greater in biopsy samples from patients with anti-TNFα agent resistance status; and stratify the results according to presence of specific genetic mutations in genes encoding ATG16 L1, NLRP3, and CARD8 (e.g., any of the mutations in the ATG16 L1 gene, NLRP3 gene, and CARD8 gene described herein).

Methods

-   Evaluation of baseline expression of NLRP3 RNA and quantify     inhibition of inflammasome activity by an NLRP3 antagonist in     biopsies of disease tissue from patients with Crohn's disease and     ulcerative colitis. -   Determine if NLRP3 antagonist treatment reduces the inflammatory     response in biopsies of disease from patients with Crohn's disease     based on decreased expression of inflammatory gene RNA measured with     Nanostring. -   Sequence patient DNA to detect specific genetic mutations in the     ATG16 L1 gene, NLRP3 gene, and CARD8 gene (e.g., any of the     exemplary mutations in these genes described herein) and then     stratify the results of functional assays according to the presence     of these genetic mutations.

Experimental Design

-   Human subjects and tissue:     -   Endoscopic or surgical biopsies from areas of disease in         patients with Crohn's disease and ulcerative colitis who are         either anti-TNFα treatment naive or resistant to anti-TNFα         treatment; additionally biopsies from control patients         (surveillance colonoscopy or inflammation-free areas from         patients with colorectal cancer) are studied. -   Ex vivo Treatment Model:     -   Organ or LPMC culture as determined appropriate -   Endpoints to be measured:     -   Before ex vivo treatment—NLRP3 RNA level     -   After ex vivo treatment—inflammasome activity (either processed         IL-1β, processed caspase-1, or secreted IL-1β); RNA for         inflammatory cytokines (Nanostring); viable T cell number and/or         T cell apoptosis. -   Data Analysis Plan:     -   Determine if NLRP3 antagonist treatment decreases processed         IL-1β, processed caspase-1 or secreted IL-1β, and inflammatory         cytokine RNA levels.     -   Stratify response data according to treatment status at biopsy         and the presence of genetic mutations in the NLRP3 gene, CARD8         gene, and ATG16 L1 gene (e.g., any of the exemplary genetic         mutations of these genes described herein).

Study Example 2 Treatment of Anti-TNFα Resistant Patients with NLRP3 Antagonists

PLoS One 2009 Nov. 24; 4(11):e7984, describes that mucosal biopsies were obtained at endoscopy in actively inflamed mucosa from patients with Ulcerative Colitis, refractory to corticosteroids and/or immunosuppression, before and 4-6 weeks after their first infliximab (an anti-TNFα agent) infusion and in normal mucosa from control patients. The patients in this study were classified for response to infliximab based on endoscopic and histologic findings at 4-6 weeks after first infliximab treatment as responder or non-responder. Transcriptomic RNA expression levels of these biopsies were accessed by the inventors of the invention disclosed herein from GSE 16879, the publically available Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/geo2r/?acc=GSE16879). Expression levels of RNA encoding NLRP3 and IL-1β were determined using GEO2R (a tool available on the same website), based on probe sets 207075_at and 205067_at, respectively. It was surprisingly found that in Crohn's disease patients that are non-responsive to the infliximab (an anti-TNFα agent) have higher expression of NLRP3 and IL-1β RNA than responsive patients (FIGS. 4 and 5 ). Similar surprising results of higher expression of NLRP3 and IL-1β RNA in UC patients that are non-responsive to infliximab (an anti-TNFα agent) compared to infliximab (an anti-TNFα agent) responsive patients (FIGS. 6 and 7 ) were found.

Said higher levels of NLRP3 and IL-1β RNA expression levels in anti-TNFα agent non-responders, is hypothesised herein to lead to NLRP3 activation which in turns leads of release of IL-1β that induces IL-23 production, leading to said resistance to anti-TNFα agents. Therefore, treatment of Crohn's and UC anti-TNFα non-responders with an NLRP3 antagonist would prevent this cascade, and thus prevent development of non-responsiveness to anti-TNFα agents. Indeed, resistance to anti-TNFα agents is common in other inflammatory or autoimmune diseases. Therefore, use of an NLRP3 antagonist for the treatment of inflammatory or autoimmune diseases will block the mechanism leading to non-responsiveness to anti-TNFα □agents. Consequently, use of NLRP3 antagonists will increase the sensitivity of patients with inflammatory or autoimmune diseases to anti-TNFα agents, resulting in a reduced dose of anti-TNFα agents for the treatment of these diseases. Therefore, a combination of an NLRP3 antagonist and an anti-TNFα agent can be used in the treatment of diseases wherein TNFα is overexpressed, such as inflammatory or autoimmune diseases, to avoid such non-responsive development of patients to anti-TNFα agents. Preferably, this combination treatment can be used in the treatment of IBD, for example Crohn's disease and UC.

Further, use of NLRP3 antagonists offers an alternative to anti-TNFα agents for the treatment of diseases wherein TNFα is overexpressed. Therefore, NLRP3 antagonists offers an alternative to anti-TNFα agents inflammatory or autoimmune diseases, such as IBD (e.g. Crohn's disease and UC).

Systemtic anti-TNFα agents are also known to increase the risk of infection. Gut restricted NLRP3 antagonists, however, offers a gut targeted treatment (i.e. non-systemic treatment), preventing such infections. Therefore, treatment of TNFα gut diseases, such as IBD (i.e. Crohn's disease and UC), with gut restricted NLRP3 antagonists has the additional advantage of reducing the risk of infection compared to anti-TNFα agents.

Proposed Experiment:

Determine the expression of NLRP3 and caspase-1 in LPMCs and epithelial cells in patients with non-active disease, in patients with active disease, in patients with active disease resistant to corticosteroids, patients with active disease resistant to TNF-blocking agents. The expression of NLRP3 and caspase-1 in LPMCs and epithelial cells will be analyzed by RNAScope technology. The expression of active NLRP3 signature genes will be analyzed by Nanostring technology. A pilot analysis to determine feasibility will be performed with 5 samples from control, 5 samples from active CD lesions, and 5 samples from active UC lesions.

Study Example 3

It is presented that NLRP3 antagonists reverse resistance to anti-TNF induced T cell depletion/apoptosis in biopsy samples from IBD patients whose disease is clinically considered resistant or unresponsive to anti-TNF therapy.

A study is designed to determine: whether NLRP3 antagonists inhibit inflammasome function and inflammatory activity in cells and biopsy specimens from patients with Crohn's disease or ulcerative colitis; and whether an NLRP3 antagonist will synergize with anti-TNFα therapy in patients with Crohn's disease or ulcerative colitis.

The secondary objectives of this study are to: determine if an NLRP3 antagonist reduces inflammasome activity in Crohn's disease and ulcerative biopsy samples (comparing Crohn's disease and ulcerative colitis results with control patient results); determine if an NLRP3 antagonist reduced inflammatory cytokine RNA and protein expression in Crohn's disease and ulcerative colitis samples; determine if an NLRP3 antagonist in the absence of co-treatment with anti-TNFα antibody induces T cell depletion in Crohn's disease and ulcerative colitis biopsy samples; and determine if baseline (no ex vivo treatment) RNA levels of NLRP3, ASC, and IL-1β are greater in biopsy samples from patients with anti-TNFα agent resistance status.

Methods

-   Evaluation of baseline expression of NLRP3 RNA and quantify     inhibition of inflammasome activity by an NLRP3 antagonist in     biopsies of disease tissue from patients with Crohn's disease and     ulcerative colitis. -   Determine if there is synergy between an NLRP3 antagonist and     anti-TNF antibody with respect to effects on T cell     depletion/apoptosis in biopsies of disease from patients with     Crohn's disease and ulcerative colitis. -   Determine if NLRP3 antagonist treatment reduces the inflammatory     response in biopsies of disease from patients with Crohn's disease     based on decreased expression of inflammatory gene RNA measured with     Nanostring.

Experimental Design

-   Human subjects and tissue:     -   Endoscopic or surgical biopsies from areas of disease in         patients with Crohn's disease and ulcerative colitis who are         either anti-TNFα treatment naive or resistant to anti-TNFα         treatment; additionally biopsies from control patients         (surveillance colonoscopy or inflammation-free areas from         patients with colorectal cancer) are studied. -   Ex vivo Treatment Model:     -   Organ or LPMC culture as determined appropriate -   Ex vivo Treatments:     -   NLRP3 antagonist (2 concentrations), negative control (vehicle),         positive control (caspase-1 inhibitor) each in the presence or         absence of anti-TNF antibody at a concentration appropriate to         distinguish differences in the T cell apoptotic between biopsies         from anti-TNF resistant and anti-TNF-sensitive Crohn's disease         patients. Each treatment condition is evaluated in a minimum in         duplicate samples. -   Endpoints to be measured:     -   Before ex vivo treatment—NLRP3 RNA level     -   After ex vivo treatment—inflammasome activity (either processed         IL-1β, processed caspase-1, or secreted IL-1β); RNA for         inflammatory cytokines (Nanostring); viable T cell number and/or         T cell apoptosis. -   Data Analysis Plan:     -   Determine if NLRP3 antagonist co-treatment increases T cell         apoptosis/deletion in response to anti-TNF.     -   Determine if the level of NLRP3 RNA expression is greater in         TNF-resistant Crohn's disease and ulcerative colitis samples         compared to anti-TNF treatment-naive samples.     -   Determine if NLRP3 antagonist treatment decreases processed         IL-1β, processed caspase-1 or secreted IL-1β, and inflammatory         cytokine RNA levels. -   Biological Assay—Nigericin-stimulated IL-1β secretion assay in THP-1     cells

Monocytic THP-1 cells (ATCC: TIB-202) were maintained according to providers' instructions in RPMI media (RPMI/Hepes +10% fetal bovine serum+Sodium Pyruvate+0.05 mM Beta-mercaptoethanol (1000× stock)+Pen-Strep). Cells were differentiated in bulk with 0.5 μM phorbol 12-myristate 13-acetate (PMA; Sigma # P8139) for 3 hours, media was exchanged, and cells were plated at 50,000 cells per well in a 384-well flat-bottom cell culture plates (Greiner, #781986), and allowed to differentiate overnight. Compound in a 1:3.16 serial dilution series in DMSO was added 1:100 to the cells and incubated for 1 hour. The NLRP3 inflammasome was activated with the addition of 15 μM (final concentration) Nigericin (Enzo Life Sciences, #BML-CA421-0005), and cells were incubated for 3 hours. 10 μL supernatant was removed, and IL-1β levels were monitored using an HTRF assay (CisBio, #62IL1PEC) according to manufacturers' instructions. Viability and pyroptosis was monitored with the addition of PrestoBlue cell viability reagent (Life Technologies, #A13261) directly to the cell culture plate.

A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims. 

What is claimed is:
 1. A compound of Formula AA

wherein m=0, 1, or 2; n=0, 1, or 2; o=1 or 2; p=0, 1, 2, or 3, wherein A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₆-C₁₀ monocyclic or bicyclic aryl; B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C₆-C₁₀ monocyclic or bicyclic aryl; wherein at least one R⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA; R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NR⁸R⁹, C(O)R¹³, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl); wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃ alkylene)C₆-C₁₀ aryl, halo, NR⁸R⁹, or oxo; wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl; or one pair of R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, 0S(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl, wherein R⁶ and R⁷ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy that R⁶ or R⁷ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl; or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; R¹⁰ is C₁-C₆ alkyl; each of R⁸ and R⁹ at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₇ cycloalkyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR^(11R12;) or R⁸ and R⁹ taken together with the nitrogen they are attached to form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆ alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy; R¹³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, or —(Z¹—Z²)_(a1)—Z³; each of R¹¹ and R¹² at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, and —(Z¹—Z²)_(a1)—Z³; a1 is 0-10 (e.g., 0-4); each Z¹ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; each Z² is independently a bond, NH, N(C₁-C₆ alkyl), —O—, —S—, or 5-10 membered heteroarylene; Z³ is independently C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy; R³ is selected from hydrogen and C₁-C₆ alkyl; R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆ alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R⁶, R¹⁵ is —(Z⁴—Z⁵)_(a2)—Z⁶; a2 is an integer selected from 1-10 (e.g., 1-5); each Z⁴ is independently selected from —O—, —S—, —NH—, and —N(C₁-C₃ alkyl)-; provided that the Z⁴ group directly attached to R¹ or R² is —O— or —S—; each Z⁵ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and Z⁶ is OH, OC₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, NHC(O)(C₁-C₆ alkyl), NHC(O)(C₁-C₆ alkoxy), or an optionally substituted group selected from the group consisting of: C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy; or a pharmaceutically acceptable salt thereof; provided that the compound is other than:


2. A compound of Formula AA

wherein m=0, 1, or 2; n=0, 1, or 2; o=1 or 2; p=0, 1, 2, or 3, wherein A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₆-C₁₀ monocyclic or bicyclic aryl; B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C₆-C₁₀ monocyclic or bicyclic aryl; wherein at least one R⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA; R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO—C₆-C₁₀ aryl, CO(5- to 10-membered heteroaryl); CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, NHCOOCC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl; wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃ alkylene)C₆-C₁₀ aryl, halo, NR⁸R⁹, or oxo; wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl; or one pair of R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl, wherein R⁶ and R⁷ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy that R⁶ or R⁷ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl; or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; R¹⁰ is C₁-C₆ alkyl; each of R⁸ and R⁹ at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₇ cycloalkyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR¹¹R¹²; or R⁸ and R⁹ taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to; R¹³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl; each of R¹¹ and R¹² at each occurrence is independently selected from hydrogen and C₁-C₆ alkyl; R³ is selected from hydrogen and C₁-C₆ alkyl; R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆ alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R⁶, R¹⁵ is —(Z⁴—Z⁵)_(a2)—Z⁶; a2 is an integer selected from 1-10 (e.g., 1-5); each Z⁴ is independently selected from —O—, —S—, —NH—, and —N(C₁-C₃ alkyl)-; provided that the Z⁴ group directly attached to R¹ or R² is —O— or —S—; each Z⁵ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and Z⁶ is OH, OC₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, NHC(O)(C₁-C₆ alkyl), NHC(O)(C₁-C₆ alkoxy), or an optionally substituted group selected from the group consisting of: C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆ alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy; or a pharmaceutically acceptable salt thereof; provided that the compound is other than:


53. A compound of Formula AA:

wherein the

moiety is as defined for (AA-1), (AA-2), (AA-3), or (AA-4) below: (AA-1): A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₇-C₁₀ bicyclic aryl; m=0, 1, or 2; and n=0, 1, or 2; (AA-2): A is phenyl; m=0, 1, or 2; and n=0, 1, or 2, provided that m+n=0, 2, 3, or 4; (AA-3):

(AA-4):

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C₆-C₁₀ monocyclic or bicyclic aryl; wherein at least one R⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA; o=1 or 2; p=0, 1, 2, or 3; when (AA-1), (AA-2), or (AA-3) applies, R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NR⁸R⁹, C(O)R¹³, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl); wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃ alkylene)C₆-C₁₀ aryl, halo, NR⁸R⁹, or oxo; wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl; or one pair of R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; OR when (AA-4) applies, R¹′ is selected from the group consisting of: methyl; C₂-C₆ alkyl; C₁-C₆ haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂; CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀ aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl; NR⁸R⁹; C(O)R¹³; CONR⁸R⁹; SF₅; SC₁-C₆ alkyl; S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl; S(O₂)NR¹¹R¹²; C₃-C₇ cycloalkyl; and 3- to 7-membered heterocycloalkyl, wherein when R¹′ is methyl, R¹′ is substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl); and when R¹′ is selected from the group consisting of C₂-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl, R¹′ is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl); wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R^(1′) C₃-C₇ cycloalkyl or of the R^(1′) 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, —O(C₀-C₃ alkylene)C₆-C₁₀ aryl, NR⁸R⁹, or oxo; wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl; R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl, wherein R⁶ and R⁷ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy that R⁶ or R⁷ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl; or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; R¹⁰ is C₁-C₆ alkyl; each of R⁸ and R⁹ at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR¹¹R¹²; or R⁸ and R⁹ taken together with the nitrogen they are attached to form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆ alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy; R¹³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, or —(Z¹—Z²)_(a1)—Z³; each of R¹¹ and R¹² at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, and —(Z¹—Z²)_(a1)—Z³; a1 is 0-10 (e.g., 0-4); each Z¹ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; each Z² is independently a bond, NH, N(C₁-C₆ alkyl), —O—, —S—, or 5-10 membered heteroarylene; Z³ is independently C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy; R³ is selected from hydrogen and C₁-C₆ alkyl (e.g., R³ is selected from hydrogen and methyl); R¹⁵ is —(Z⁴—Z⁵)_(a2)—Z⁶; a2 is an integer selected from 1-10 (e.g., 1-5); each Z⁴ is independently selected from —O—, —S—, —NH—, and —N(C₁-C₃ alkyl)-; provided that the Z⁴ group directly attached to R¹ or R² is —O— or —S—; each Z⁵ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and Z⁶ is OH, OC₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, NHC(O)(C₁-C₆ alkyl), NHC(O)(C₁-C₆ alkoxy), or an optionally substituted group selected from the group consisting of: C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆ alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy; or a pharmaceutically acceptable salt thereof.
 4. A compound of Formula AA

wherein the

moiety is as defined for (AA-1), (AA-2), (AA-3), or (AA-4) below: (AA-1): A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₇-C₁₀ bicyclic aryl; m=0, 1, or 2; and n=0, 1, or 2; (AA-2): A is phenyl; m=0, 1, or 2; and n=0, 1, or 2, provided that m+n=0, 2, 3, or 4; (AA-3):

(AA-4):

B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C₆-C₁₀ monocyclic or bicyclic aryl; wherein at least one R⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA; o=1 or 2; p=0, 1, 2, or 3; when (AA-1), (AA-2), or (AA-3) apply, R¹ and R² are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO—C₆-C₁₀ aryl, CO(5- to 10-membered heteroaryl); CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, NHCOOCC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl; wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃ alkylene)C₆-C₁₀ aryl, halo, NR⁸R⁹, or oxo; wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl; or one pair of R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; OR when (AA-4) applies, R¹′ is selected from the group consisting of: methyl; C₂-C₆ alkyl; C₁-C₆ haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; NO₂; COC₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀ aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; NHCOC₁-C₆ alkyl; NHCOC₆-C₁₀ aryl; NHCO(5- to 10-membered heteroaryl); NHCO(3- to 7-membered heterocycloalkyl); NHCOC₂-C₆ alkynyl; NHCOOC₁-C₆ alkyl; NH—(C═NR¹³)NR¹¹R¹²; CONR⁸R⁹; SF₅; SC₁-C₆ alkyl; S(O₂)C₁-C₆ alkyl; S(O)C₁-C₆ alkyl; S(O₂)NR¹¹R¹²; C₃-C₇ cycloalkyl; and 3- to 7-membered heterocycloalkyl, wherein when R¹′ is methyl, R¹′ is substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl); wherein when R¹′ is selected from the group consisting of C₂-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl, R¹′ is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl; wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R¹′ C₃-C₇ cycloalkyl or of the R¹′ 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃ alkylene)C₆-C₁₀ aryl, halo, NR⁸R⁹, or oxo; wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl; R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl, wherein R⁶ and R⁷ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy that R⁶ or R⁷ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl; or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; R¹⁰ is C₁-C₆ alkyl; each of R⁸ and R⁹ at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR¹¹R¹²; or R⁸ and R⁹ taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to; R¹³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl; each of R¹¹ and R¹² at each occurrence is independently selected from hydrogen and C₁-C₆ alkyl; R³ is selected from hydrogen and C₁-C₆ alkyl (e.g., R³ is selected from hydrogen and methyl); R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆ alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R⁶; R¹⁵ is —(Z⁴—Z⁵)_(2a)—Z⁶; a2 is an integer selected from 1-10 (e.g., 1-5); each Z⁴ is independently selected from —O—, —S—, —NH—, and —N(C₁-C₃ alkyl)-; provided that the Z⁴ group directly attached to R¹ or R² is —O— or —S—; each Z⁵ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and Z⁶ is OH, OC₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, NHC(O)(C₁-C₆ alkyl), NHC(O)(C₁-C₆ alkoxy), or an optionally substituted group selected from the group consisting of: C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy; or a pharmaceutically acceptable salt thereof.
 5. A compound of Formula AA

wherein m=1 or 2; n=1 or 2; o=1 or 2; p=0, 1, 2, or 3, wherein A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₆-C₁₀ monocyclic or bicyclic aryl; B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C₆-C₁₀ monocyclic or bicyclic aryl; wherein at least one R⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA; one pair of R¹ and R² are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; each of R¹ and R² that are not taken together with the atoms connecting them to form at least one ring is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NR⁸R⁹, C(O)R¹³, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl); wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃ alkylene)C₆-C₁₀ aryl, halo, NR⁸R⁹, or oxo; wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl; R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl, wherein R⁶ and R⁷ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy that R⁶ or R⁷ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl; or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; R¹⁰ is C₁-C₆ alkyl; each of R⁸ and R⁹ at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR¹¹R¹²; or R⁸ and R⁹ taken together with the nitrogen they are attached to form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy; R¹³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, or —(Z¹—Z²)_(a1)—Z³; each of R¹¹ and R¹² at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, and —(Z¹—Z²)_(a1)—Z³; a1 is 0-10 (e.g., 0-4); each Z¹ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; each Z² is independently a bond, NH, N(C₁-C₆ alkyl), —O—, —S—, or 5-10 membered heteroarylene; Z³ is independently C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy; R³ is selected from hydrogen and C₁-C₆ alkyl (e.g., R³ is selected from hydrogen and methyl); R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆ alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R⁶, R¹⁵ is —(Z⁴—Z⁵)_(a2)—Z⁶; a2 is an integer selected from 1-10 (e.g., 1-5); each Z⁴ is independently selected from —O—, —S—, —NH—, and —N(C₁-C₃ alkyl)-; provided that the Z⁴ group directly attached to R¹ or R² is —O— or —S—; each Z⁵ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and Z⁶ is OH, OC₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, NHC(O)(C₁-C₆ alkyl), NHC(O)(C₁-C₆ alkoxy), or an optionally substituted group selected from the group consisting of: C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆ alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy; or a pharmaceutically acceptable salt thereof.
 6. A compound of Formula AA

wherein m=1 or 2; n=1 or 2; o=1 or 2; p=0, 1, 2, or 3, wherein A is a 5- to 10-membered monocyclic or bicyclic heteroaryl or a C₆-C₁₀ monocyclic or bicyclic aryl; B is a 5-membered heteroaryl, a 7-10 membered monocyclic or bicyclic heteroaryl, or a C₆-C₁₀ monocyclic or bicyclic aryl; wherein at least one R⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula AA; one pair of R¹ and R² are on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹,═NR¹⁰,CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; each of R¹ and R² that are not taken together with the atoms connecting them to form at least one ring is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO—C₆-C₁₀ aryl, CO(5- to 10-membered heteroaryl); CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, NHCOOCC₁-C₆ alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, S(O)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl; wherein each C₁-C₆ alkyl substituent and each C₁-C₆ alkoxy substituent of the R¹ or R² C₃-C₇ cycloalkyl or of the R¹ or R² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃ alkylene)C₆-C₁₀ aryl, halo, NR⁸R⁹, or oxo; wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl; R⁶ and R⁷ are each independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, NO₂, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆ alkyl, N(C₁-C₆ alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆ alkyl, S(O₂)C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆ alkenyl, wherein R⁶ and R⁷ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆ alkynyl, C₆-C₁₀ aryloxy, and S(O₂)C₁-C₆ alkyl; and wherein the C₁-C₆ alkyl or C₁-C₆ alkoxy that R⁶ or R⁷ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀ aryl or NR⁸R⁹, or wherein R⁶ or R⁷ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, and OC₁-C₆ alkyl; or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈ carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; R¹⁰ is C₁-C₆ alkyl; each of R⁸ and R⁹ at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR¹¹R¹²; or R⁸ and R⁹ taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to; R¹³ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl; each of R¹¹ and R¹² at each occurrence is independently selected from hydrogen and C₁-C₆ alkyl; R³ is selected from hydrogen and C₁-C₆ alkyl (e.g., R³ is selected from hydrogen and methyl); R¹⁴ is hydrogen, C₁-C₆ alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C₆-C₁₀ monocyclic or bicyclic aryl, wherein each C₁-C₆ alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R⁶, R¹⁵ is —(Z⁴—Z⁵)_(a2)—Z⁶; a2 is an integer selected from 1-10 (e.g., 1-5); each Z⁴ is independently selected from —O—, —S—, —NH—, and —N(C₁-C₃ alkyl)-; provided that the Z⁴ group directly attached to R¹ or R² is —O— or —S—; each Z⁵ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and Z⁶ is OH, OC₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, NHC(O)(C₁-C₆ alkyl), NHC(O)(C₁-C₆ alkoxy), or an optionally substituted group selected from the group consisting of: C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy; or a pharmaceutically acceptable salt thereof.
 7. The compound of any one of claims 5-6, provided that the compound is not selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 8. The compound of any one of claims 1-7, wherein: (1) one or more of R¹ or R², when present, is selected from N^(8′)R^(9′), C(O)NR^(8′)R^(9′), S(O)₂NR^(11′)R^(12′), C(O)R^(13′), C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-C₁₀ aryl, and 5- to 10-membered heteroaryl, wherein each of the C₃-C₇ cycloalkyl, and 3- to 7-membered heterocycloalkyl is substituted with NR^(8′)R^(9′), C(O)NR^(8′)R^(9′), R^(15′), C₁-C₆ haloalkoxy, or C₃-C₇ cycloalkyl; wherein each of the C₁-C₆ alkyl and C₁-C₆ haloalkyl is substituted with NR^(8′)R^(9′), C(O)NR^(8′)R^(9′), R¹⁵, C₁-C₆ haloalkoxy, or C₃-C₇ cycloalkyl; and each of the C₁-C₆ alkoxy, C₆-C₁₀ aryl and 5- to 10-membered heteroaryl is substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, R¹⁵, C₁-C₆ haloalkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₃-C₇ cycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl); or (2) one pair of R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one ring that is selected from: (a) C₄-C₈ carbocyclic ring or 5- to-8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is independently substituted with one or more substituents each independently selected from from C₂-C₆ alkenyl, C₂-C₆ alkynyl, OC₃-C₁₀ cycloalkyl, CN, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl, wherein the S(O₂)C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; (b) C₄-C₈ carbocyclic ring or 5- to-8-membered heterocyclic ring containing 3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; and (c) monocyclic or bicyclic C₉-C₁₂ carbocyclic ring or monocyclic or bicyclic 9- to 12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; each of R^(8′) and R^(9′) at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₂-C₆ alkenyl, (C═NR¹³)NR¹¹R¹²; S(O₂)C₁-C₆ alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³ and CONR¹¹R¹²; wherein the C₁-C₆ alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆ alkoxy, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR¹¹R¹²; or R^(8′) and R^(9′) taken together with the nitrogen they are attached to form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy; provided that: (1) one or more occurrences of R^(8′) or R^(9′) is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₇ cycloalkyl, (C═NR^(13′))NR^(11′)R^(12′), S(O₂)NR^(11′)R^(12′); C(O)R^(13′), CO₂R^(13′) and CONR^(11′)R^(12′); wherein the C₁-C₆ alkyl is substituted with NR¹¹R¹²; or (2) one or more pairs of R^(8′) and R^(9′) attached to the same nitrogen taken together with the nitrogen they are attached to form: (a) a 8- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy; or (b) a 3- to 7-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy; each of R^(11′) and R^(12′) at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl, and —(Z¹—Z²)_(a1)—Z³, provided that one or more occurrences of R^(11′) and R^(12′) is —(Z¹—Z²)_(a1)—Z³; R^(13′) is —(Z¹—Z²)_(a1)—Z^(3′), wherein when a1 is 0, Z^(3′) is independently C₆₋₁₀ aryl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, each of which is substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxy; when a1 is 1-10 (e.g., 1-4), Z^(3′) is an independently selected Z³; R¹⁵′ is —(Z⁴—Z⁵)_(a2′)—Z⁶; a2′ is an integer selected from 2-10 (e.g., 2-5); each Z⁴ is independently selected from —O—, —S—, —NH—, and —N(C₁-C₃ alkyl)-; provided that the Z⁴ group directly attached to R¹ or R² is —O— or —S—; each Z⁵ is independently C₁-C₆ alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and Z⁶ is OH, OC₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, NHC(O)(C₁-C₆ alkyl), NHC(O)(C₁-C₆ alkoxy), or an optionally substituted group selected from the group consisting of: C₆-C₁₀ aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C₁-C₆ alkyl, C₁₋₆ haloalkyl, C₁-C₆ alkoxy, oxo, N(C₁-C₆ alkyl)₂, NH₂, NH(C₁-C₆ alkyl), and hydroxyl.
 9. The compound of any one of claims 1-8, wherein when a pair of R¹ and R² on adjacent atoms, taken together with the atoms connecting them, independently form one C₄-C₈ carbocyclic ring or one 5- to-8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, then the carbocyclic ring or heterocyclic ring is independently substituted with one or more substituents each independently selected from from C₂-C₆ alkenyl, C₂-C₆ alkynyl, OC₃-C₁₀ cycloalkyl, CN, OS(O₂)C₆-C₁₀ aryl, S(O₂)C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl, wherein the S(O₂)C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 10. The compound of any one of claims 3-4, wherein the

moiety is as defined for (AA-1).
 11. The compound of any one of claims 1-10, wherein A is a 5- to 6-membered monocyclic heteroaryl optionally substituted with 1 or 2 R¹ and optionally substituted with 1 or 2 R².
 12. The compound of any one of claims 1-11, wherein A is furanyl optionally substituted with 1 or 2 R¹ and optionally substituted with 1 or 2 R².
 13. The compound of any one of claims 1-11, wherein A is thiophenyl optionally substituted with 1 or 2 R¹ and optionally substituted with 1 or 2 R².
 14. The compound of any one of claims 1-11, wherein A is oxazolyl optionally substituted with 1 or 2 R¹ and optionally substituted with 1 or 2 R².
 15. The compound of any one of claims 1-11, wherein A is thiazolyl optionally substituted with 1 or 2 R¹ and optionally substituted with 1 or 2 R².
 16. The compound of any one of claims 1-11, wherein A is pyrazolyl optionally substituted with 1 or 2 R¹ and optionally substituted with 1 or 2 R².
 17. The compound of any one of claims 1-11, wherein A is imidazolyl optionally substituted with 1 or 2 R¹ and optionally substituted with 1 or 2 R².
 18. The compound of any one of claims 3-4, wherein the

moiety is as defined for (AA-2), (AA-3), or (AA-4) (e.g., (AA-2) or (AA-3)).
 19. The compound of any one of claims 1-9 and 18, wherein A is phenyl optionally substituted with 1 or 2 R¹ and optionally substituted with 1 or 2 R².
 20. The compound of any one of claims 1-4, 8, and 10-19, wherein m=1 and n=0.
 21. The compound of any one of claims 1-4, 8, 10-11, 13, and 20, wherein A is


22. The compound of any one of claims 1-4, 8, 10-11, 13, and 20, wherein A is


23. The compound of any one of claims 1-4, 8, 10-12, and 20, wherein A is


24. The compound of any one of claims 1-4, 8, 10-12, and 20, wherein A is


25. The compound of any one of claims 1-4, 8, 10-11, 15, and 20, wherein A is


26. The compound of any one of claims 1-4, 8, 10-11, 15, and 20, wherein A is


27. The compound of any one of claims 1-4, 8, 10-11, 15, and 20, wherein A is


28. The compound of any one of claims 1-4, 8, and 18-20, wherein A is


29. The compound of any one of claims 1-4, 8, and 18-20, wherein A is


30. The compound of any one of claims 1-4, 8, and 18-20, wherein A is


31. The compound of any one of claims 1-4 and 10, wherein A is


32. The compound of any one of claims 1-4, 10, 16, and 20, wherein A is


33. The compound of any one of claims 1-4, 8, 10-11, and 20, wherein A is


34. The compound of any one of claims 1-4, 8, 10-11, and 20, wherein A is


35. The compound of any one of claims 1-4, 8, 10-11, and 20, wherein A is


36. The compound of any one of claims 1-19, wherein m=1 and n=1.
 37. The compound of any one of claims 1-11, 13, and 36, wherein A is


38. The compound of any one of claims 1-4, 8, 10-11, 15, and 36, wherein A is


39. The compound of any one of claims 1-4, 8, 10-11, 15, and 36, wherein A is


40. The compound of any one of claims 1-12 and 36, wherein A is


41. The compound of any one of claims 1-11, 13, and 36, wherein A is


42. The compound of any one of claims 1-4, 10-11, 13, and 36, wherein A is


43. The compound of any one of claims 1-11, 15, and 36, wherein A is


44. The compound of any one of claims 1-11, 16, and 36, wherein the optionally substituted ring A is


45. The compound of any one of claims 1-11, 16, and 36, wherein the optionally substituted ring A is


46. The compound of any one of claims 1-11, 16, and 36, wherein the optionally substituted ring A is


47. The compound of any one of claims 1-11, 17, and 36, wherein the optionally substituted ring A is


48. The compound of any one of claims 1-4, 8, 18-19, and 36, wherein A is


49. The compound of any one of claims 1-4, 8, 18-19, and 36, wherein A is


50. The compound of any one of claims 1-9, 18-19, and 36, wherein A is


51. The compound of any one of claims 1-4, 8, 18-19, and 36, wherein A is


52. The compound of any one of claims 1-4, 8, 18-19, and 36, wherein A is


53. The compound of any one of claims 1-19, wherein m=2 and n=1.
 54. The compound of any one of claims 1-4, 8, 18-19 and 53, wherein A is


55. The compound of any one of claims 1-9, 18-19, and 53, wherein A is


56. The compound of any one of claims 1-9, 18-19, and 53, wherein A is


57. The compound of any one of claims 1-9, 18-19, and 53, wherein A is


58. The compound of any one of claims 1-11, 16, and 53, wherein A is


59. The compound of any one of claims 1-4 and 10-58, wherein each of R¹ and R², when present, is independently selected from the group consisting of C₁-C₆ alkyl optionally substituted with one or more hydroxy, halo, oxo, C₁-C₆ alkoxy, 3- to 7-membered heterocycloalkyl optionally substituted with halo, C₃-C₇ cycloalkyl, R¹⁵, C₁-C₆ haloalkoxy, C₆-C₁₀ aryl optionally substituted with OC₁-C₆ alkyl, or NR⁸R⁹; C₃-C₇ cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C₁-C₆ alkoxy, C₁-C₆ alkyl, or NR⁸R⁹ wherein the C₁-C₆ alkoxy or C₁-C₆ alkyl is further optionally substituted with one to three hydroxy, halo, NR⁸R⁹, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C₁-C₆ alkyl, or NR⁸R⁹ wherein the C₁-C₆ alkoxy or C₁-C₆ alkyl is further optionally substituted with one to three hydroxy, halo, NR⁸R⁹, or oxo; C₁-C₆ haloalkyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; halo; CN; CO—C₁-C₆ alkyl; CO—C₆-C₁₀ aryl; CO(5- to 10-membered heteroaryl); CO₂C₁-C₆ alkyl; CO₂C₃-C₈ cycloalkyl; OCOC₁-C₆ alkyl; OCOC₆-C₁₀ aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C₆-C₁₀ aryl; 5- to 10-membered heteroaryl; NH₂; NHC₁-C₆ alkyl; N(C₁-C₆ alkyl)₂; CONR⁸R⁹; SF₅; S(O₂)NR¹¹R¹²; S(O)C₁-C₆ alkyl; and S(O₂)C₁-C₆ alkyl.
 60. The compound of any one of claims 1-4 and 10-58, wherein R¹ is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; isobutyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; 1,2,3-trihydroxy-2-propyl; 1-amino-2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; 1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl; 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl; 1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; 1-(2-methoxyethoxy)-2-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; pyrrolidinyl; 1,3-dioxolan-2-yl; COCH₃; COCH₂CH₃; difluoromethoxy; 2-methoxy-2-propyl; (methylamino)methyl; (2,2-difluoroeth-1-yl)(methyl)aminomethyl; (2,2,2-trifluoroeth-1-yl)(methyl)aminomethyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; 2-((methyl)aminomethyl)-prop-2-yl; 2-((methyl)amino)-prop-2-yl; (methyl)(cyclopropylmethyl)aminomethyl; (methyl)(2-(dimethylamino)eth-1-yl)aminomethyl; (cyclobutyl)(methyl)aminomethyl; 1-(cyclobutyl)amino-eth-1-yl; isopropylaminomethyl; (cyclobutyl)aminomethyl; cycloheptylaminomethyl; tetrahydropyranylaminomethyl; sec-butylaminomethyl; ethylaminomethyl; allylaminomethyl; (2,2-difluoroeth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)(methyl)aminomethyl; 2-fluoro-1-dimethylamino-eth-1-yl; 1-dimethylamino-2,2-difluoroeth-1-yl; 1-dimethylamino-2,2,2-trifluoroeth-1-yl; 1-dimethylamino-2,2,2-trimethyleth-1-yl; dimethylamino(cyclopropyl)methyl; methoxymethyl; isopropyl(methyl)amino; fluoro; chloro; phenyl; pyridyl; pyrazolyl; azetidinyl; 5-methyl-oxazolidin-2-one-5-yl; S(O₂)CH₃; S(O₂)NR¹¹R¹²; (3,3-difluoropyrrolidin-1-yl)methyl; 1-(difluoromethoxyl)eth-1-yl; azetidinylmethyl; 1-((methyl)aminomethyl)-cycloprop-1-yl; 4-methoxybenzyl; 4-methyl-piperazin-1-yl; morpholinylmethyl; and cyclopentyl.
 61. The compound of any one of claims 59-60, wherein R² is selected from the group consisting of fluoro, chloro, cyano, methyl; methoxy; ethoxy; isopropyl; 1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; COCH₃; COPh; 2-methoxy-2-propyl; methoxymethyl; (dimethylamino)methyl; S(O₂)CH₃; and S(O₂)NR¹¹R¹².
 62. The compound of any one of claims 1-4 and 10-59, wherein one or more R¹ when present is independently a C₁-C₆ alkyl substituted with one or more hydroxy.
 63. The compound of claim 62, wherein one or more R¹ is independently selected from 1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; and 1,2,3-trihydroxy-2-propyl
 64. The compound of any one of claims 1-4 and 10-59, wherein one or more R¹ when present is independently a C₁-C₆ alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) NR⁸R⁹.
 65. The compound of claim 64, wherein one or more R¹ is independently selected from 1-amino-2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; and 1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl.
 66. The compound of any one of claims 1-4 and 10-59, wherein one or more R¹ when present is independently a C₁-C₆ alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) R¹⁵.
 67. The compound of claim 66, wherein one or more R¹ is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl; 1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.
 68. The compound of any one of claims 1-4 and 10-59, wherein one or more R¹ is independently C₁-C₆ alkyl substituted with one or more (e.g., one) NR⁸R⁹ and further optionally substituted with one or more halo.
 69. The compound of claim 68, wherein one or more R¹ is independently selected from: (methylamino)methyl; (2,2-difluoroeth-1-yl)(methyl)aminomethyl; (2,2,2-trifluoroeth-1-yl)(methyl)aminomethyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; 2-((methyl)aminomethyl)-prop-2-yl; 2-((methyl)amino)-prop-2-yl; (methyl)(cyclopropylmethyl)aminomethyl; (methyl)(2-(dimethylamino)eth-1-yl)aminomethyl; (cyclobutyl)(methyl)aminomethyl; 1-(cyclobutyl)amino-eth-1-yl; isopropylaminomethyl; (cyclobutyl)aminomethyl; cycloheptylaminomethyl; tetrahydropyranylaminomethyl; sec-butylaminomethyl; ethylaminomethyl; allylaminomethyl; (2,2-difluoroeth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)(methyl)aminomethyl; 2-fluoro-1-dimethylamino-eth-1-yl; 1-dimethylamino-2,2-difluoroeth-1-yl; 1-dimethylamino-2,2,2-trifluoroeth-1-yl; 1-dimethylamino-2,2,2-trimethyleth-1-yl; and dimethylamino(cyclopropyl)methyl (e.g., one or more R¹ is dimethylaminomethyl or methylaminomethyl).
 70. The compound of any one of claims 62-69, wherein one or more R² is independently selected from C₁-C₆ alkyl, C₁-C₆ alkyl optionally substituted with one or more hydroxy, C₁-C₆ alkyl optionally substituted with one or more C₁-C₆ alkoxy, and halo.
 71. The compound of any one of claims 1-7, 10-19, 36-37, 40-41, 43-47, 50, 53, and 55-58, wherein one pair of R¹ and R² is on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring (e.g., C₅ or C₆ carbocyclic ring) or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 (e.g., 1-2, e.g., 2) heteroatoms independently selected from O, N, and S (e.g., tetrahydropyridine, dihydrofuran, or dihydropyran), wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl (e.g., methyl), C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy (e.g., methoxy, ethoxy, isopropoxyl), OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or oxetanyl), and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo (e.g., fluoro), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹ (e.g., amino, methylamino, or dimethylamino), ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 72. The compound of any one of claims 1-7, 10-19, 36-37, 40-41, 43-47, 50, 53, and 55-58 wherein one pair of R¹ and R² is on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₅-C₆ carbocyclic ring wherein the carbocyclic is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino; or one pair of R¹ and R² on adjacent atoms taken together forms a moiety selected from:

each of which is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino.
 73. The compound of any one of claims 1-7, 10-19, 36-37, 40-41, 43-47, 50, 53, and 55-58, wherein one pair of R¹ and R² is on adjacent atoms, and taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic C₄-C₁₂ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino.
 74. The compound of any one of claims 1-7, 10-19, 36-37, 40-41, 43-47, 50, 53, and 55-58, wherein one pair of R¹ and R² is on adjacent atoms, and taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino.
 75. The compound of any one of claims 1-6, wherein the optionally substituted ring A is selected from the group consisting of a 5-membered heteroaryl comprising 2 or more heteroatoms, a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH, and NR¹, and a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the S(O)(NHR³)═N moiety; m is 1; n is 1; R¹ and R² are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 76. The compound of any one of claims 1-6, wherein the optionally substituted ring A is a pyrazolyl; m is 1; n is 1; R¹ and R² are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 77. The compound of any one of claims 1-6, wherein the optionally substituted ring A is an imidazolyl; m is 1; n is 1; R¹ and R² are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 78. The compound of any one of claims 1-6, wherein the optionally substituted ring A is a thiophenyl; m is 1; n is 1; R¹ and R² are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 79. The compound of any one of claims 1-6, wherein the optionally substituted ring A is a thiazolyl; m is 1; n is 1; R¹ and R² are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂ carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, OC₃-C₁₀ cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆ alkyl, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O₂)C₆-C₁₀ aryl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₁₀ cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₆ alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 80. The compound of any one of claims 1-6, wherein the optionally substituted ring A is

wherein R^(x) is selected from the group consisting of H and C₁-C₆ alkyl (e.g., methyl); Z¹ is selected from the group consisting of O, NH, and —CH₂— optionally substituted with 1-2 R²⁰; Z² is selected from the group consisting of NH and —CH₂— optionally substituted with 1-2 R²⁰; Z³ is selected from the group consisting of —CH₂— optionally substituted with 1-2 R²⁰, —CH₂CH₂— optionally substituted with 1-2 R²⁰, and —CH₂CH₂CH₂— optionally substituted with 1-2 R²⁰; R²⁰ is selected from the group consisting of hydroxy, halo (e.g., fluoro), oxo, C₁-C₆ alkyl (e.g., methyl or ethyl) optionally substituted with one R²¹, C₁-C₆ alkoxy (e.g., methoxy, ethoxy, or isopropoxy) optionally substituted with one R²¹, NR⁸R⁹, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or pyrrolidinyl) optionally substituted with one R²¹, or one pair of R²⁰ on the same atom, taken together with the atom connecting them, independently forms a monocyclic C₃-C₄ carbocyclic ring or a monocyclic 3- to 4-membered heterocyclic ring containing 1 O atom optionally substituted with OS(O)₂Ph; R²¹ is selected from the group consisting of halo (e.g., fluoro), NR⁸R⁹, C₂-C₆ alkynyl (e.g., ethynyl), and C₁-C₆ alkoxy (e.g., methoxy); R⁸ and R⁹ at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl (e.g., methyl or ethyl), COR¹³, and CO₂R¹³; R¹³ is selected from the group consisting of: C₁-C₆ alkyl (e.g., methyl or t-butyl) and C₁-C₆ haloalkyl (e.g., trifluoromethyl).
 81. The compound of any one of claims 1-6, wherein the optionally substituted ring A is

wherein Z⁴ is selected from the group consisting of —CH₂—, —C(O)—, and NH; Z⁵ is selected from the group consisting of O, NH, N—CH₃, and —CH₂—.
 82. The compound of any one of the preceding claims, wherein B is phenyl substituted with 1 or 2 R⁶ and optionally substituted with 1, 2, or 3 R⁷.
 83. The compound of claim 82, wherein o=2 and p=0.
 84. The compound of any one of claims 82-83, wherein B is


85. The compound of claim 84, wherein each R⁶ is independently selected from the group consisting of: C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl.
 86. The compound of any one of claims 84 and 85, wherein each R⁶ is independently selected from the group consisting of: C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₃-C₇ cycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, or oxo.
 87. The compound of claim 82, wherein o=1 and p=1.
 88. The compound of claim 82, wherein o=2 and p=1.
 89. The compound of claim 88, wherein B is


90. The compound of claim 88, wherein B is


91. The compound of claim 88, wherein B is


92. The compound of any one of claims 89-91, wherein each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl; wherein R⁷ is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is optionally substituted with one to two C₁-C₆ alkoxy; or R⁶ and R⁷, taken together with the atoms connecting them, independently form C₄-C₇ carbocyclic ring or at least one 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 93. The compound of claim 88, wherein B is


94. The compound of claim 93, wherein each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃-C₇ cycloalkyl, and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl; wherein R⁷ is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is optionally substituted with one to two C₁-C₆ alkoxy.
 95. The compound of claim 82, wherein o=2 and p=2.
 96. The compound of claim 95, wherein B is


97. The compound of claim 95, wherein B is


98. The compound of any one of claims 96-97, wherein each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl; wherein each R⁷ is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is optionally substituted with one to two C₁-C₆ alkoxy; or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₇ carbocyclic ring or at least one 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 99. The compound of any one of claims 95-98, wherein two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and each pair of one R⁶ and one R⁷ taken together with the atoms connecting them independently form a C₄-C₇ carbocyclic ring or a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein each carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 100. The compound of any one of claims 96-99, wherein one pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₅ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 101. The compound of claim 100, wherein the other pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₅ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 102. The compound of any one of claims 96 and 99-101, wherein the substituted ring B is:


103. The compound of any one of claims 97 and 99-101, wherein the substituted ring B is:


104. The compound of claim 100, wherein the other pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₄ or C₆₋₇ (e.g., C₄) carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 105. The compound of claim 104, wherein the substituted ring B is:


106. The compound of any one of claims 96-99, wherein one pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₄ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 107. The compound of claim 106, wherein the other pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₄ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 108. The compound of claim 107, wherein the substituted ring B is:


109. The compound of any one claims 96 and 98, wherein one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form one C₄-C₇ carbocyclic ring or one 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; and each of the remaining R⁶ and R⁷ is independently selected from C₁-C₆ alkyl and C₃-C₇ cycloalkyl.
 110. The compound of claim 109, wherein one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form one C₄-C₇ (e.g., C₅) carbocyclic ring; and each of the remaining R⁶ and R⁷ is independently selected from C₁-C₆ alkyl and C₃-C₇ cycloalkyl.
 111. The compound of claim 110, wherein the substituted ring B is


112. The compound of claim 95, wherein B is


113. The compound of claim 112, wherein each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl; wherein each R⁷ is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is optionally substituted with one to two C₁-C₆ alkoxy; or R⁶ and R⁷, taken together with the atoms connecting them, independently form C₄-C₇ carbocyclic ring or at least one 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 114. The compound of claim 82, wherein o=2 and p=3
 115. The compound of claim 114, wherein B is


116. The compound of claim 115, wherein each R⁶ is independently selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆ alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆ alkyl, NHCOC₆-C₁₀ aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆ alkynyl; wherein each R⁷ is independently selected from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is optionally substituted with one to two C₁-C₆ alkoxy; or at least one pair of R⁶ and R⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₇ carbocyclic ring or at least one 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 117. The compound of any one of claims 114-116, wherein two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and each pair of one R⁶ and one R⁷ taken together with the atoms connecting them independently form a C₄-C₇ carbocyclic ring or a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein each carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 118. The compound of any one of claims 114-117, wherein one pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₅ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 119. The compound of claim 118, wherein the other pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₅ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 120. The compound of claim 119, wherein the substituted ring B is:


121. The compound of claim 120, wherein R⁷ is selected from each R⁷ is independently selected from C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, and CN.
 122. The compound of any one of the preceding claims, wherein R³ is hydrogen.
 123. The compound of any one of claims 1-121, wherein R³ is methyl.
 124. The compound of any one of claims 1-6, wherein the optionally substituted ring A is

wherein R^(x) is selected from the group consisting of H and C₁-C₆ alkyl (e.g., methyl); Z¹ is selected from the group consisting of O, NH, and —CH₂— optionally substituted with 1-2 R²⁰; Z² is selected from the group consisting of NH and —CH₂— optionally substituted with 1-2 R²⁰; Z³ is selected from the group consisting of —CH₂— optionally substituted with 1-2 R²⁰, —CH₂CH₂— optionally substituted with 1-2 R²⁰, and —CH₂CH₂CH₂— optionally substituted with 1-2R²⁰; R²⁰ is selected from the group consisting of hydroxy, halo (e.g., fluoro), oxo, C₁-C₆ alkyl (e.g., methyl or ethyl) optionally substituted with one R²¹, C₁-C₆ alkoxy (e.g., methoxy, ethoxy, or isopropoxy) optionally substituted with one R²¹, NR⁸R⁹, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or pyrrolidinyl) optionally substituted with one R²¹, or one pair of R²⁰ on the same atom, taken together with the atom connecting them, independently forms a monocyclic C₃-C₄ carbocyclic ring or a monocyclic 3- to 4-membered heterocyclic ring containing 1 O atom optionally substituted with OS(O)₂Ph; R²¹ is selected from the group consisting of halo (e.g., fluoro), NR⁸R⁹, C₂-C₆ alkynyl (e.g., ethynyl), and C₁-C₆ alkoxy (e.g., methoxy); R⁸ and R⁹ at each occurrence is independently selected from hydrogen, C₁-C₆ alkyl (e.g., methyl or ethyl), COR¹³, and CO₂R¹³; R¹³ is selected from the group consisting of: C₁-C₆ alkyl (e.g., methyl or t-butyl) and C₁-C₆ haloalkyl (e.g., trifluoromethyl); and the substituted ring B is selected from:

wherein two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and each pair of one R⁶ and one R⁷ taken together with the atoms connecting them independently form a C₄-C₇ carbocyclic ring or a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein each carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; and the remaining R⁷ that is not taken with a R⁶ on adjacent atoms to form a C₄-C₇ carbocyclic ring or a 5- to 7-membered heterocyclic ring is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is optionally substituted with one to two C₁-C₆ alkoxy.
 125. The compound of any one of claims 1-6, wherein the optionally substituted ring A is

wherein Z⁴ is selected from the group consisting of —CH₂—, —C(O)—, and NH; Z⁵ is selected from the group consisting of O, NH, N—CH₃, and —CH₂—; and the substituted ring B is selected from:

wherein two pairs, each of one R⁶ and one R⁷, are on adjacent atoms, and each pair of one R⁶ and one R⁷ taken together with the atoms connecting them independently form a C₄-C₇ carbocyclic ring or a 5- to 7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein each carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹; and the remaining R⁷ that is not taken with a R⁶ on adjacent atoms to form a C₄-C₇ carbocyclic ring or a 5- to 7-membered heterocyclic ring is independently selected from C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halo, CN, COC₁-C₆ alkyl, CO₂C₁-C₆ alkyl, CO₂C₃-C₆ cycloalkyl, OCOC₁-C₆ alkyl, OCOC₆-C₁₀ aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, CONR⁸R⁹, SF₅, S(O₂)C₁-C₆ alkyl, C₃-C₇ cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆ alkyl is optionally substituted with one to two C₁-C₆ alkoxy.
 126. The compound of any one of claims 124-125, wherein the substituted ring B is


127. The compound of any one of claims 124-125, wherein the substituted ring B is


128. The compound of any one of claims 124-127, wherein one pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₅ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 129. The compound of claim 128, wherein the other pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₅ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 130. The compound of claim 128, wherein wherein the other pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₄ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 131. The compound of any one of claims 124-128, wherein one pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₄ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 132. The compound of claim 131, wherein wherein the other pair of R⁶ and R⁷ taken together with the atoms connecting them independently form a C₄ carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆ alkyl, C₆-C₁₀ aryl, and CONR⁸R⁹.
 133. The compound of any one of claims 126 and 128-129, wherein the substituted ring B is selected from:


134. The compound of any one of claims 126, 128, and 130, wherein the substituted ring B is:


135. The compound of any one of claims 126 and 131-132, wherein the substituted ring B is:


136. The compound of any one of claims 127 and 128-129, wherein the substituted ring B is:


137. A compound selected from the group consisting of the compounds below: Cmpd # Structure 101′

101

102

103′

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

163

164

165

166

167

168

169

170

171

172

172a

172b

173

173a

173b

174

175

176

176a

176b

177

177a

177b

178

178a

178b

179

179a

179b

180

180a

180b

181

181a

181b

182

182a

182b

183

183a

183b

184

185

185a

185b

186

186a

186b

187

187a

187b

188

188a

188b

189

189a

189b

190

190a

190b

191

192

192a

192b

193

193a

193b

and pharmaceutically acceptable salts thereof.
 138. A compound selected from the group consisting of the compounds below: Cmpd # Structure 105a

105b

106a

106b

107a

107b

108a

108b

109a

109b

110a

110b

112a

112b

116a

116b

120a

120b

121a

121b

122a

122b

125a

125b

129a

129b

130a

130b

131a

131b

134a

134b

135a

135b

136a

136b

143a

143b

144a

144b

145a

145b

148a

148b

149a

149b

151a′

151b′

151a

151b

152a

152b

153a

153b

154a

154b

157b

158a

158b

161a

161b

165a

165b

167a

167b

168a

168b

170a

170b

171a

171b

174a

174b

191a

191b

195

195a

195ba

195bb

196

197

198

200

202

202a

202b

205

205a

205b

206

206a

206b

207

207a

207b

208

209

211

212

212a

212b

213

216

220

220a

220b

221

223a

223b

225a

225b

270

and pharmaceutically acceptable salts thereof.
 139. A compound selected from the group consisting of the compounds in the following table: 113a

334a

113b

335

137a

335b

137b

335a

138a

336

138b

336a

139a

336b

139b

337

159a

337b

159ba

338

159ab

338a

195e

339

207bb

339a

207aa

340

207c

340a

303

340b

303a

341

303b

341b

306

342

307

343

308

343a

308a

343b

308b

344

309

345

310

346

311

347

312

348

313

349

314

350

315

351

315b

352

315a

352b

316

352a

316b

353

317

354

317ab

354a

317aa

354b

317bb

355

317ba

356

318

357

318a

357a

318b

357b

319

358

319ab

359

319ba

359a

319aa

360ba

319bb

360bb

320

361b

320a

363b

320b

363a

321

364a

321b

364b

321a

365a

322

365b

323

366a

323ab

366b

323aa

367a

323bb

367b

323ba

369a

324

369b

325

371b

325a

372b

325b

373b

326

375

326b

375a

326a

375b

327

376

328b

376a

328a

376b

329

377

329a

378

329b

379

330

379a

330a

379b

330b

380

331

380a

332

380b

332a

380c

332b

380d

333

382

333a

382a

333b

382b

334

383

334ba

383a

334bb

383b

334aa

384a

334ab

384b

334b

387a

334a

387b

and pharmaceutically acceptable salts thereof.
 140. A compound selected from the group consisting of the compounds in the table below: 501

618

502

619

503

620

504

621

505

622

506

623

507

624

508

625

509

626

510

627

511

628

512

629

513

630

514

631

515

632

516

633

517

634

518

635

519

636

520

637

521

638

522

639

523

640

524

641

525

642

526

643

527

644

528

645

529

646

530

647

531

648

532

649

533

650

534

651

535

652

536

653

537

654

538

655

539

656

540

657

541

658

542

659

543

660

544

661

545

662

546

663

547

664

548

665

549

666

550

667

551

668

552

669

553

670

554

671

555

672

556

673

557

674

558

675

559

676

560

677

561

678

562

679

563

680

564

681

565

682

566

683

567

684

568

685

569

686

570

687

571

688

572

689

573

690

574

691

575

692

576

693

577

694

578

695

579

696

580

697

581

698

582

699

583

700

584

701

585

702

586

703

587

704

588

705

589

706

590

707

591

708

592

709

593

710

594

711

595

712

596

713

597

714

598

715

599

716

600

717

601

718

602

719

603

720

604

721

605

722

606

723

607

724

608

725

609

726

610

727

611

728

612

729

613

730

614

731

615

732

616

733

617

734

735

and pharmaceutically acceptable salts thereof.
 141. A compound selected from the group consisting of the compounds in Table 1C and pharmaceutically acceptable salts thereof.
 142. A compound selected from the group consisting of the compounds in Table 1D or Table 1E (e.g., Table 1D; e.g., Table 1E) and pharmaceutically acceptable salts thereof
 143. A compound selected from the group consisting of the following 411

412a

411a

413

412

413a

and pharmaceutically acceptable salts thereof.
 144. The compound of any one of the preceding claims, wherein the sulfur in the moiety S(═O)(NHR³)═N— has (S) stereochemistry.
 145. The compound of any one of claims 1 to 143, wherein the sulfur in the moiety S(═O)(NHR³)═N— has (R) stereochemistry.
 146. A pharmaceutical composition comprising a compound or salt as claimed in any one of claims 1-145 and one or more pharmaceutically acceptable excipients.
 147. A method for modulating NLRP3 activity, the method comprising contacting NLRP3 with an effective amount of a compound as claimed in any one of claims 1-145 or a pharmaceutical composition as claimed in claim
 146. 148. The method of claim 147, wherein the modulating comprises antagonizing NLRP3.
 149. The method of any one of claim 147 or 148, which is carried out in vitro.
 150. The method of claims 147 to 149, wherein the method comprises contacting a sample comprising one or more cells comprising NLRP3 with the compound.
 151. The method of any one of claim 147, 148 or 150, which is carried out in vivo.
 152. The method of claim 151, wherein the method comprises administering the compound to a subject having a disease in which NLRP3 signaling contributes to the pathology and/or symptoms and/or progression of the disease.
 153. The method of claim 152, wherein the subject is a human.
 154. A method of treating a disease, disorder or condition that is a metabolic disorder, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-145 or a pharmaceutical composition as claimed in claim
 146. 155. The method of claim 154, wherein the metabolic disorder is Type 2 diabetes, atherosclerosis, obesity or gout.
 156. A method of treating a disease, disorder or condition that is a disease of the central nervous system, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-145 or a pharmaceutical composition as claimed in claim
 146. 157. The method of claim 156, wherein the disease of the central nervous system is Alzheimer's disease, multiple sclerosis, Amyotrophic Lateral Sclerosis or Parkinson's disease.
 158. A method of treating a disease, disorder or condition that is lung disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-145 or a pharmaceutical composition as claimed in claim
 146. 159. The method of claim 158, wherein the lung disease is asthma, COPD or pulmonary idiopathic fibrosis.
 160. A method of treating a disease, disorder or condition that is liver disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-145 or a pharmaceutical composition as claimed in claim
 146. 161. The method of claim 160, wherein the liver disease is NASH syndrome, viral hepatitis or cirrhosis.
 162. A method of treating a disease, disorder or condition that is pancreatic disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-145 or a pharmaceutical composition as claimed in claim
 146. 163. The method of claim 162, wherein the pancreatic disease is acute pancreatitis or chronic pancreatitis.
 164. A method of treating a disease, disorder or condition that is kidney disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-145 or a pharmaceutical composition as claimed in claim
 146. 165. The method of claim 164, wherein the kidney disease is acute kidney injury or chronic kidney injury.
 166. A method of treating a disease, disorder or condition that is intestinal disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-145 or a pharmaceutical composition as claimed in claim
 146. 167. The method of claim 166, wherein the intestinal disease is Crohn's disease or Ulcerative Colitis.
 168. A method of treating a disease, disorder or condition that is skin disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-145 or a pharmaceutical composition as claimed in claim
 146. 169. The method of claim 168, wherein the skin disease is psoriasis.
 170. A method of treating a disease, disorder or condition that is musculoskeletal disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-145 or a pharmaceutical composition as claimed in claim
 146. 171. The method of claim 170, wherein the musculoskeletal disease is scleroderma.
 172. A method of treating a disease, disorder or condition that is a vessel disorder, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-145 or a pharmaceutical composition as claimed in claim
 146. 173. The method of claim 172, wherein the vessel disorder is giant cell arteritis.
 174. A method of treating a disease, disorder or condition that is a disorder of the bones, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-145 or a pharmaceutical composition as claimed in claim
 146. 175. The method of claim 174, wherein the disorder of the bones is osteoarthritis, osteoporosis or osteopetrosis disorders.
 176. A method of treating a disease, disorder or condition that is eye disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-145 or a pharmaceutical composition as claimed in claim
 146. 177. The method of claim 176, wherein the eye disease is glaucoma or macular degeneration.
 178. A method of treating a disease, disorder or condition that is a disease caused by viral infection, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-145 or a pharmaceutical composition as claimed in claim
 146. 179. The method of claim 178, wherein the diseases caused by viral infection is HIV or AIDS.
 180. A method of treating a disease, disorder or condition that is an autoimmune disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-145 or a pharmaceutical composition as claimed in claim
 146. 181. The method of claim 180, wherein the autoimmune disease is Rheumatoid Arthritis, Systemic Lupus Erythematosus, Autoimmune Thyroiditis.
 182. A method of treating a disease, disorder or condition that is cancer or aging, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-145 or a pharmaceutical composition as claimed in claim
 146. 183. A method of treating a disease, disorder or condition that is a cancer selected from: myelodysplastic syndromes (MDS); non-small cell lung cancer, such as non-small cell lung cancer in patients carrying mutation or overexpression of NLRP3; acute lymphoblastic leukemia (ALL), such as ALL in patients resistant to glucocorticoids treatment; Langerhan's cell histiocytosis (LCH); multiple myeloma; promyelocytic leukemia; acute myeloid leukemia (AML); chronic myeloid leukemia (CML); gastric cancer; and lung cancer metastasis, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-145 or a pharmaceutical composition as claimed in claim
 146. 184. The method of claim 183, wherein the cancer is MDS.
 185. The method of claim 183, wherein the cancer is non-small lung cancer.
 186. The method of claim 183, wherein the cancer is acute lymphoblastic leukemia.
 187. The method of claim 183, wherein the cancer is LCH.
 188. The method of claim 183, wherein the cancer is multiple myeloma.
 189. The method of claim 183, wherein the cancer is promyelocytic leukemia.
 190. The method of claim 183, wherein the cancer is acute myeloid leukemia (AML).
 191. The method of claim 183, wherein the cancer is chronic myeloid leukemia (CML).
 192. The method of claim 183, wherein the cancer is gastric cancer.
 193. The method of claim 183, wherein the cancer is lung cancer metastasis.
 194. The method of any one of claims 152-193, further comprising administering a therapeutically effective amount of an anti-TNFα agent to the subject.
 195. The method of claim 194, wherein the NLRP3 antagonist is administered to the subject prior to administration of the anti-TNFα agent to the subject.
 196. The method of claim 194, wherein the anti-TNFα agent is administered to the subject prior to the administration of the NLRP3 antagonist to the subject.
 197. The method of claim 194, wherein the NLRP3 antagonist and the anti-TNFα agent are administered to the subject at substantially the same time.
 198. The method of claim 194, wherein the NLRP3 antagonist and the anti-TNFα agent are formulated together in a single dosage form. 